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Alejandro Villagra - One of the best experts on this subject based on the ideXlab platform.
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abstract 4967 HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid derived suppressor cells transition
Cancer Research, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Alejandro Villagra, Zi Wang, Javier Pinillaibarz, Eduardo SotomayorAbstract:In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells. Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells. Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4967.
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Histone Deacetylase 11 (HDAC11) Interaction with Ikaros Represent a Novel Mechanism of Regulation of Essential Transcriptional Factors in CD4+ T Cells
Blood, 2016Co-Authors: Jie Chen, Edward Seto, Fengdong Cheng, David M Woods, Alejandro Villagra, Eduardo M. SotomayorAbstract:Histone deacetylase 11 (HDAC11), the most recently identified histone deacetylase, is the sole member of class IV HDACs [1]. Since its discovery, no biological function was assigned to this HDAC until we demonstrated its central role in negatively regulating IL-10 production in antigen presenting cells (APCs) [2]. More recently, we have found that disruption of HDAC11 in T cells is associated with an enhanced pro-inflammatory cytokine profile and effector molecule production. Furthermore, T-cells lacking HDAC11 were less susceptible to regulatory T-cell (Treg) suppression in vitro, were refractory to tolerance induction in vivo and displayed enhanced allo-reactivity and anti-tumor responses in murine models. Of note, T-cells lacking HDAC11 expressed higher levels of the transcription factors Eomes and Tbet. Conversely, overexpression of HDAC11 in T-cells decreased the expression of both transcription factors. The molecular mechanism(s) by which HDAC11 regulates the expression of these transcription factors have remained unknown. By using chromatin immunoprecipitation (ChIP) assay we found that in resting T-cells HDAC11 is present at the Eomes and Tbet gene promoters where it maintains histone deacetylation, a compacted chromatin and gene repression. Following T-cell stimulation, HDAC11 was largely absent from both promoters, which resulted in increased histone 3 (H3) acetylation and gene transcriptional activity. These findings were confirmed in T-cells isolated from HDAC11 knock out (KO) mice which also displayed an increase in H3 acetylation at the Tbet and Eomes gene promoter regions. Conversely, H3 acetylation was decreased in both gene promoters in T-cells overexpressing HDAC11 as compared to empty-vector transfected cells. Given that HDACs do not bind to DNA, we asked next which transcription factor(s) HDAC11 might be associated with, in order to regulate Tbet and Eomes gene transcriptional activity. In prior studies we have found that HDAC11 form a molecular complex with another member of the HDAC family, HDAC6, which physically interacts with the transcription factor, STAT3 in both the cytoplasmic and nuclear compartments. However, in T-cells no direct interaction of HDAC11 with STAT3 was detected in either compartment. In contrast, we found for the first time that HDAC11 physically associates with Ikaros (Ikzf1), a member of the Ikaros zinc finger transcription factor family that has been previously implicated in the regulation of T-bet gene expression and IFN-g production in T-cells [3-5]. The protein complex HDAC11-Ikaros was mainly detected in the nuclear compartment and both proteins were present at the T-bet gene promoter. Collectively, these results point to the HDAC11-Ikaros complex as a novel epigenetic mechanism of regulation of Tbet and Eomes, transcription factors that are essential for T cell development and function. Disclosures Woods:BMS: Other: Stock; HDAC11: Patents & Royalties: Patent for targeting HDAC11; Lion Biotech: Other: Stock.
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Functional Analysis of Histone Deacetylase 11 (HDAC11).
Methods in molecular biology (Clifton N.J.), 2016Co-Authors: Jie Chen, Eva Sahakian, John Powers, Maritza Lienlaf, Patricio Perez-villarroel, Tessa Knox, Alejandro VillagraAbstract:The physiological role of histone deacetylase 11 (HDAC11), the newest member of the HDAC family, remained largely unknown until the discovery of its regulatory function in immune cells. Among them, the regulation of cytokine production by antigen-presenting cells and the modulation of the suppressive ability of myeloid-derived suppressor cells (MDSCs) (Sahakian et al. Mol Immunol 63: 579-585, 2015; Wang et al. J Immunol 186: 3986-3996, 2011; Villagra et al. Nat Immunol 10: 92-100, 2009). Our earlier data has demonstrated that HDAC11, by interacting at the chromatin level with the IL-10 promoter, downregulates il-10 transcription in both murine and human APCs in vitro and ex vivo models (Villagra et al. Nat Immunol 10: 92-100, 2009). However the role of HDAC11 in other cell types still remains unknown. Here we present several methods that can potentially be used to identify the functional role of HDAC11, assigning special attention to the evaluation of immunological parameters.
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A Novel Role for Histone Deacetylase 11 (HDAC11) in B Cell Lymphopoiesis and Plasma Cell Survival in Multiple Myeloma
Blood, 2014Co-Authors: Jason Brayer, Eva Sahakian, John Powers, Allison Distler, Mark B. Meads, Susan Deng, Melissa Alsina, Taiga Nishihori, Rachid Baz, Alejandro VillagraAbstract:While multiple myeloma (MM) remains incurable presently, expanded therapeutic options over the past decade have improved patient survival markedly. Proteasome inhibitors have redefined the treatment paradigm for myeloma, often serving as the backbone of front-line treatment. Histone deacetylase (HDAC) inhibitors (HDI), although only marginally active as single agent therapy in hematological malignancies, have demonstrated an ability to salvage bortezomib responsiveness in refractory patients, prompting heightened interest in this class of targeted therapeutics in myeloma. HDAC’s represent a family of enzymes, currently with 11 known members in the classical HDAC family, and subdivided into 4 sub-classes. HDAC11 is currently the only member of the sub-class IV and, as the newest member of the HDAC family, its impact on B cell lymphopoiesis and myeloma development is only starting to be unveiled. Intriguingly, we show that mice with germ-line silencing of HDAC11 (HDAC11KO mice) exhibit a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Consistent with this, Tg-HDAC11-eGFP mice, a transgenic strain engineered to express GFP under control of the HDAC11 promoter (Heinz, N Nat. Rev. Neuroscience 2001) reveals that HDAC11 expression is increased in the plasma cell population and to a lesser extent B1 B cells, as compared to earlier lineage stages. Similar observations based on measurements of HDAC11 mRNA were seen in normal human plasma cells. Significant increases in HDAC11 mRNA expression were observed in 7 of 11 primary human multiple myeloma samples and 11 of 12 human myeloma cell lines as compared to normal plasma cells, further emphasizing the potential relevance of HDAC11 to the underlying pathologic processes driving myeloma development and/or survival. Targeted silencing of HDAC11 in RPMI-8226 cells lines using siRNA results in a modest decrease in cell viability as measured by Annexin/PI staining and detection of activated caspase-3. Quisinostat, a second generation pan-HDI, has previously demonstrated activity against human myeloma cell lines in vitro (Stuhmer, Brit J Haematol, 2010), and suppressed bone destruction in an in vivo murine myeloma model (Deleu, Cancer Res, 2009). We similarly observe dose-dependent survival impairment in 10 human myeloma cell lines when cultured in the presence of quisinostat, with EC50’s consistently in the 1-10nM range. Importantly, quisinostat acts synergistically with proteasome inhibitiors (bortezomib and carfilzomib) in RPMI-8226 cells; more importantly, the degree of synergism is amplified in the RPMI-6226-B25 bortezomib-resistant cell line. Although a clear mechanism of action remains to be elucidated, preliminary data suggests that RPMI-8226 cells exposed to quisinostat appear to exhibit a decrease nuclear, but not cytosolic HDAC11. Collectively, these data illustrate a previously unknown role for HDAC11 in plasma cell differentiation and survival. Increased HDAC11 expression seen in myeloma patient specimens and primary myeloma cell lines highlights the potential of HDAC11 as a therapeutic target. Furthermore, we show that quisinostat, a pan-HDI with selectivity towards HDAC11 at lower dosing, acts synergistically with proteasome inhibitors in vitro in proteasome inhibitor sensitive and resistant cell lines. Future work will focus on further elucidating the role of HDAC11 in myeloma survival and drug response, with particular emphasis on proteasome inhibitors. Disclosures No relevant conflicts of interest to declare.
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Histone Deacetylase 11 (HDAC11) As a Novel Transcriptional Regulator of C/EBP-β, in Immature Myeloid Cell to Myeloid Derived Suppressor Cell Transition
Blood, 2014Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Allison Distler, Alejandro Villagra, Susan Deng, Maritza Lienlaf-moreno, Limin Xing, Pedro HornaAbstract:In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, dendritic cells, and neutrophils. However, in pathological conditions such as in cancer, these immature cells differentiate into myeloid derived suppressor cells (MDSCs). Transcription factor CCAAT-enhancer-binding protein beta (C/EBP-β) plays a crucial role in the accumulation of MDSCs in several pathological conditions. Of note, mice lacking C/EBP-β in the bone marrow compartment lose the ability to differentiate IMCs into pathologically active MDSCs2.In contrast, up-regulation of C/EBP-β can partly induce MDSC expansion through a mechanism involving the STAT3 pathway3. Epigenetic changes, such as histone acetylation status, have been recently shown to modulate the regulatory function of MDSCs4. However, the epigenetic mechanism(s) involved in regulation of C/EBP-β gene expression in MDSCs are poorly understood. Here we show for the first time that among all the HDACs known, HDAC11, the newest member of this family of enzymes, is recruited to the C/EBP-β gene promoter region of primary myeloid cells isolated from C57BL/6 mice. Such a finding led us to explore the functional consequences of disrupting HDAC11 in myeloid cells. First, we observed a markedly higher expression of C/EBP-β mRNA (194 fold difference) in the CD11b+/Ly6G+ granulocytic compartment and a 6.7 fold difference in the CD11b+/Ly6C+monocytic compartments of HDAC11KO mice relative to control wild type mice. Second, MDSCs from HDAC11 KO mice display a higher suppressive phenotype and mechanistically we have found that they have increased expression of the immunosuppressive STAT3/IL10 axis. Third, inoculation of EL4 tumor cells into HDAC11KO mice and controls resulted in a higher expansion capacity of splenic MDSCs in mice devoid of HDAC11. Such an effect was associated with a more rapid tumor growth in HDAC11KO mice as compared to WT mice. Similar aggressive tumor growth was also observed in HDAC11 myeloid conditional KO mice (LyZ-Cre-HDAC11KO). Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of C/EBP-β in MDSCs. Indeed, in the absence of this epigenetic checkpoint of C/EBP-β gene expression, the fully suppressive potential of MDSCs was fully unleashed. A better understanding of this novel role of HDAC11 in myeloid biology will ultimately lead to targeted epigenetic therapies to manipulate the suppressive abilities of these immunoregulatory cells. 1. Hirai H, Zhang P, Dayaram T, et al. C/EBPbeta is required for 9emergency9 granulopoiesis. Nat Immunol 2006; 7(7): 732-9. 2. Marigo I, Bosio E, Solito S, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 2010; 32(6): 790-802. 3. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32(1): 19-25. 4. Youn JI, Kumar V, Collazo M, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 2013; 14(3): 211-20. Disclosures No relevant conflicts of interest to declare.
Eva Sahakian - One of the best experts on this subject based on the ideXlab platform.
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HDAC11 regulates expression of c ebpβ and immunosuppressive molecules in myeloid derived suppressor cells
Journal of Leukocyte Biology, 2021Co-Authors: Jie Chen, Edward Seto, Eva Sahakian, John Powers, Fengdong Cheng, Jianguo Tao, Zi Wang, Javier Pinillaibarz, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells derived from bone marrow and negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previously we have demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increased suppressive activity against CD8+ T-cells. However, the mechanisms of HDAC11 that contribute to the suppressive function of MDSCs remain unclear. Here, we show that arginase activity and NO production is significantly higher in HDAC11 knockout MDSCs when compared with wild-type (WT) controls. In the absence of HDAC11, elevated arginase level and enzymatic activity were observed preferentially in the tumor-infiltrated granulocytic MDSCs, whereas iNOS expression and NO production were increased in the tumor-infiltrated monocytic MDSCs. Of note and for the first time, we demonstrated an association between the elevated expression of immunosuppressive molecules with up-regulation of the transcription factor C/EBPβ in MDSCs lacking HDAC11. Interestingly, the highest expression of C/EBPβ was observed among CD11b+ Gr-1+ MDSCs isolated from tumor-bearing mice. The additional demonstration that HDAC11 is recruited to the promoter region of C/EBPβ in WT MDSCs suggests a novel molecular mechanism by which HDAC11 influence the expression of immunosuppressive molecules in MDSCs through regulation of C/EBPβ gene expression.
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HDAC11 deficiency disrupts oncogene induced hematopoiesis in myeloproliferative neoplasms
Blood, 2020Co-Authors: Lanzhu Yue, Christelle M. Colin, Vasundhara Sharma, Nathan P Horvat, Afua A Akuffo, Matthew Beatty, Cem Murdun, Julia M R Billington, William E Goodheart, Eva SahakianAbstract:Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although HDAC11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, HDAC11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.
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functional analysis of HDAC11 in plasma cell development and multiple myeloma survival
Blood, 2018Co-Authors: A G M Mostofa, Eva Sahakian, John Powers, Allison Distler, Mark B. Meads, Melissa Alsina, Taiga Nishihori, Rachid Baz, Tuan Nguyen, Javier Pinilla IbarzAbstract:Abstract Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissection of the roles of individual HDAC isoforms to best target plasma cell malignancies with minimal toxicity. HDAC11 was recently found to regulate function in key immune cell populations including regulatory T cells, effector T cells, neutrophils, and myeloid-derived suppressor cells (MDSC). Though HDAC11 expression is confirmed in B cells and plasma cells, its functions in these cells remain largely unknown. In this study, we attempted a functional analysis of HDAC11 in plasma cell development along with its pro-tumorigenic function in MM cells. Methods: Mouse models, including a transgenic mouse strain expressing eGFP under the regulation of the HDAC11 promoter (Tg-HDAC11-eGFP), and also an HDA11-deficient mouse (B6.HDAC11-/-) were studied to establish the importance of HDAC11 in plasma cell biology. Pharmacologic inhibition of HDAC11 in MM cell lines was accomplished by using elevenostat, a new HDAC11-selective inhibitor in comparison with pan-inhibitors quisinostat and panobinostat. Impact on viability in human-derived MM cell lines was assessed using the CCK-8 assay, while induction of cell death was measured via detection of activated Caspase-3 and annexin/propidium iodide staining by flow cytometry. Synergy studies were performed by following the Chou-Talalay method for drug combinations. Post-translational modifications and subcellular localization changes induced by HDIs exposure were assessed by western blotting of fractionated cell lysates, while immunoprecipitation and proximity ligation assays (in situ PLA) were used to identify a binding partner for HDAC11. Results: Studies in Tg-HDAC11-eGFP mice reveal that HDAC11 expression in B cell lymphopoiesis is minimally detectable prior to B cell activation but demonstrates strong induction upon maturation into a plasma cell. Consistent with this, plasma cell development is markedly impaired in the absence of HDAC11. The HDAC11-selective inhibitor elevenostat showed significant cytotoxic potential in different MM cell lines that express moderate to high level of HDAC11, with IC50 values ranging 0.6-2.0 µM. Consistently, MM cell lines expressing null/very low level of HDAC11 were insensitive to elevenostat. Moreover, combining elevenostat with proteasome inhibitors bortezomib (BTZ) and carfilzomib resulted in significant synergistic effects evident from combination index (CI) and dose-reduction index (DRI) values measured by CompuSyn software. Elevenostat was also able to re-sensitize BTZ-resistant sub-clones (e.g., RPMI-8226-B25, KAS-6-V10R, and ANBL6-V10R) to BTZ and exhibited superior synergistic effects. Furthermore, elevenostat-treated cells showed a time-dependent alteration in the subcellular localization of HDAC11. HDAC11 gradually disappeared from the nuclear fractions with simultaneous upregulation in cytoplasmic fractions; similar observations were made from pan HDIs (quisinostat and panobinostat) treatment. However, unlike pan HDIs, the elevenostat treatment caused global downregulation of HDAC11 in some MM cell lines at the later time points (72 or 96 hrs), suggesting differential effects of various HDIs. Inhibition of HDAC11 also caused downstream suppression of several pro-tumorigenic factors of MM cells including IRF4 and c-Myc. Additionally, a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was identified by using PLA. HDAC11 dynamically interacts with IRF4 which can be induced by LPS stimulation and inhibited by HDIs, indicating the involvement of HDAC11 in the IRF4-mediated regulatory circuit. Conclusions: We observe that targeted inhibition of HDAC11 can impair MM cell survival and overcome acquired resistance to proteasome inhibitors. Furthermore, we identify IRF4 as a nuclear binding partner of HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and survival. Disclosures No relevant conflicts of interest to declare.
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Loss of HDAC11 Promotes Myeloid-Derived Suppressor Cells Inhibition of T Cell Function in a Murine Lymphoma Microenvironment
Blood, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Michael Wang, Javier Pinilla Ibarz, Mitchell R. Smith, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells constitute a heterogeneous population of immature myeloid cells derived from bone marrow that negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previous work in our lab had demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increase in suppressive activity against IFN-γ producing CD8+ T cells. The upregulated suppressive activity of HDAC11KO MDSCs was associated with a more aggressive tumor growth pattern when compared with wild type control mice. Mechanistically we have found that tumor infiltrated HDAC11KO MDSCs isolated from lymphoma-bearing mice displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function, when compare with wild type MDSCs. However, both arginase activity and NO production were at a similar level in the wild type and HDAC11KO MDSCs isolated from spleens of the same lymphoma-bearing mice. This finding suggests that HDAC11KO MDSCs are more suppressive within the tumor microenvironment. Moreover, the aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been previously shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of both MDSC and/or T-cells from either wild type or HDAC11 KO mice into C57BL/6 lymphoma-bearing animals. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the HDAC11KO T cells in the lymphoma microenvironment Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs phenotype and function in a murine lymphoma model. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells in vivo. Disclosures No relevant conflicts of interest to declare.
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abstract 4967 HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid derived suppressor cells transition
Cancer Research, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Alejandro Villagra, Zi Wang, Javier Pinillaibarz, Eduardo SotomayorAbstract:In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells. Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells. Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4967.
John Powers - One of the best experts on this subject based on the ideXlab platform.
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HDAC11 regulates expression of c ebpβ and immunosuppressive molecules in myeloid derived suppressor cells
Journal of Leukocyte Biology, 2021Co-Authors: Jie Chen, Edward Seto, Eva Sahakian, John Powers, Fengdong Cheng, Jianguo Tao, Zi Wang, Javier Pinillaibarz, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells derived from bone marrow and negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previously we have demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increased suppressive activity against CD8+ T-cells. However, the mechanisms of HDAC11 that contribute to the suppressive function of MDSCs remain unclear. Here, we show that arginase activity and NO production is significantly higher in HDAC11 knockout MDSCs when compared with wild-type (WT) controls. In the absence of HDAC11, elevated arginase level and enzymatic activity were observed preferentially in the tumor-infiltrated granulocytic MDSCs, whereas iNOS expression and NO production were increased in the tumor-infiltrated monocytic MDSCs. Of note and for the first time, we demonstrated an association between the elevated expression of immunosuppressive molecules with up-regulation of the transcription factor C/EBPβ in MDSCs lacking HDAC11. Interestingly, the highest expression of C/EBPβ was observed among CD11b+ Gr-1+ MDSCs isolated from tumor-bearing mice. The additional demonstration that HDAC11 is recruited to the promoter region of C/EBPβ in WT MDSCs suggests a novel molecular mechanism by which HDAC11 influence the expression of immunosuppressive molecules in MDSCs through regulation of C/EBPβ gene expression.
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functional analysis of HDAC11 in plasma cell development and multiple myeloma survival
Blood, 2018Co-Authors: A G M Mostofa, Eva Sahakian, John Powers, Allison Distler, Mark B. Meads, Melissa Alsina, Taiga Nishihori, Rachid Baz, Tuan Nguyen, Javier Pinilla IbarzAbstract:Abstract Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissection of the roles of individual HDAC isoforms to best target plasma cell malignancies with minimal toxicity. HDAC11 was recently found to regulate function in key immune cell populations including regulatory T cells, effector T cells, neutrophils, and myeloid-derived suppressor cells (MDSC). Though HDAC11 expression is confirmed in B cells and plasma cells, its functions in these cells remain largely unknown. In this study, we attempted a functional analysis of HDAC11 in plasma cell development along with its pro-tumorigenic function in MM cells. Methods: Mouse models, including a transgenic mouse strain expressing eGFP under the regulation of the HDAC11 promoter (Tg-HDAC11-eGFP), and also an HDA11-deficient mouse (B6.HDAC11-/-) were studied to establish the importance of HDAC11 in plasma cell biology. Pharmacologic inhibition of HDAC11 in MM cell lines was accomplished by using elevenostat, a new HDAC11-selective inhibitor in comparison with pan-inhibitors quisinostat and panobinostat. Impact on viability in human-derived MM cell lines was assessed using the CCK-8 assay, while induction of cell death was measured via detection of activated Caspase-3 and annexin/propidium iodide staining by flow cytometry. Synergy studies were performed by following the Chou-Talalay method for drug combinations. Post-translational modifications and subcellular localization changes induced by HDIs exposure were assessed by western blotting of fractionated cell lysates, while immunoprecipitation and proximity ligation assays (in situ PLA) were used to identify a binding partner for HDAC11. Results: Studies in Tg-HDAC11-eGFP mice reveal that HDAC11 expression in B cell lymphopoiesis is minimally detectable prior to B cell activation but demonstrates strong induction upon maturation into a plasma cell. Consistent with this, plasma cell development is markedly impaired in the absence of HDAC11. The HDAC11-selective inhibitor elevenostat showed significant cytotoxic potential in different MM cell lines that express moderate to high level of HDAC11, with IC50 values ranging 0.6-2.0 µM. Consistently, MM cell lines expressing null/very low level of HDAC11 were insensitive to elevenostat. Moreover, combining elevenostat with proteasome inhibitors bortezomib (BTZ) and carfilzomib resulted in significant synergistic effects evident from combination index (CI) and dose-reduction index (DRI) values measured by CompuSyn software. Elevenostat was also able to re-sensitize BTZ-resistant sub-clones (e.g., RPMI-8226-B25, KAS-6-V10R, and ANBL6-V10R) to BTZ and exhibited superior synergistic effects. Furthermore, elevenostat-treated cells showed a time-dependent alteration in the subcellular localization of HDAC11. HDAC11 gradually disappeared from the nuclear fractions with simultaneous upregulation in cytoplasmic fractions; similar observations were made from pan HDIs (quisinostat and panobinostat) treatment. However, unlike pan HDIs, the elevenostat treatment caused global downregulation of HDAC11 in some MM cell lines at the later time points (72 or 96 hrs), suggesting differential effects of various HDIs. Inhibition of HDAC11 also caused downstream suppression of several pro-tumorigenic factors of MM cells including IRF4 and c-Myc. Additionally, a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was identified by using PLA. HDAC11 dynamically interacts with IRF4 which can be induced by LPS stimulation and inhibited by HDIs, indicating the involvement of HDAC11 in the IRF4-mediated regulatory circuit. Conclusions: We observe that targeted inhibition of HDAC11 can impair MM cell survival and overcome acquired resistance to proteasome inhibitors. Furthermore, we identify IRF4 as a nuclear binding partner of HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and survival. Disclosures No relevant conflicts of interest to declare.
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Loss of HDAC11 Promotes Myeloid-Derived Suppressor Cells Inhibition of T Cell Function in a Murine Lymphoma Microenvironment
Blood, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Michael Wang, Javier Pinilla Ibarz, Mitchell R. Smith, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells constitute a heterogeneous population of immature myeloid cells derived from bone marrow that negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previous work in our lab had demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increase in suppressive activity against IFN-γ producing CD8+ T cells. The upregulated suppressive activity of HDAC11KO MDSCs was associated with a more aggressive tumor growth pattern when compared with wild type control mice. Mechanistically we have found that tumor infiltrated HDAC11KO MDSCs isolated from lymphoma-bearing mice displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function, when compare with wild type MDSCs. However, both arginase activity and NO production were at a similar level in the wild type and HDAC11KO MDSCs isolated from spleens of the same lymphoma-bearing mice. This finding suggests that HDAC11KO MDSCs are more suppressive within the tumor microenvironment. Moreover, the aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been previously shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of both MDSC and/or T-cells from either wild type or HDAC11 KO mice into C57BL/6 lymphoma-bearing animals. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the HDAC11KO T cells in the lymphoma microenvironment Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs phenotype and function in a murine lymphoma model. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells in vivo. Disclosures No relevant conflicts of interest to declare.
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abstract 4967 HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid derived suppressor cells transition
Cancer Research, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Alejandro Villagra, Zi Wang, Javier Pinillaibarz, Eduardo SotomayorAbstract:In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells. Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells. Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4967.
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HDAC11 is a candidate therapeutic target in multiple myeloma
Blood, 2017Co-Authors: Jason Brayer, Eva Sahakian, John Powers, Allison Distler, Mark B. Meads, Melissa Alsina, Taiga Nishihori, Rachid Baz, Tuan Nguyen, Javier PinillaibarzAbstract:Background: Histone deacetylase (HDAC) inhibitors (HDI), although only marginally active as single agent therapy in multiple myeloma (MM), demonstrate an ability to salvage proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) responsiveness in refractory patients, thus raising interest in this class of targeted therapeutics. Selective inhibition of particular HDAC isoforms may further improve therapeutic efficacy. HDAC11, the newest member of the HDAC family, is expressed in a progressive manner during B cell development with greatest expression in mature plasma cells (PC). Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11-/-) or targeted to the B cell lineage (CD19Cre.HDAC11-/-). In vitro assays were completed using established human myeloma cell lines that include RPMI-8226, RPMI-8226-B25, OPM2, H929, KMS11, KMS28, KAS6, KAS6R10R, MM1.S, and MM1R10R (kind gift from Dr. Orlowski). Inhibition of HDAC11 in MM cell lines was accomplished by both molecular and pharmacologic approaches. Viability was measured according to activated caspase-3 and Annexin/PI staining by flow cytometry, and by CCK-8 viability assay. Subcellular localization changes induced by HDI exposure were assessed by Western Blot of fractionated cell lysates, while immunoprecipitation and confocal microscopy, using both immunofluorescence and proximity ligation assay techniques, were used to identify IRF4 as a novel nuclear binding partner for HDAC11. Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. Consistent with this, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11-/- mice, where HDAC11 ablation is restricted to the B cell lineage, suggests activity inherent in B cells rather than via externally derived signals. Initial studies evaluating the effects of quisinostat, a second-generation HDI with increased selectivity that includes HDAC11, showed dose-dependent cytotoxicity versus 10 myeloma cell lines with EC50 measurements in the 1-10nM range. This activity was synergistic with BTZ and carfilzomib (CFZ) in RPMI-8226 cells and degree of synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Subsequent experiments using HDTK-010 (FORMA Therapeutics), an HDAC11-selective HDI, showed dose-dependent cytotoxicity in 21 MM cell lines (EC50 1-10mM). Targeted siRNA-mediated silencing of HDAC11 in RPMI-8226 cells yielded a reduction in cell viability, as measured by Annexin/PI staining and detection of activated caspase-3. An important interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was first identified by immunoprecipitation assay in 8226 cells. This interaction has been confirmed by confocal microscopy using immunofluorescent co-localization and proximity ligation techniques in 8226, MM1.S, OPM2 and H929 cell lines as well as in CD138-enriched MM cells from patient marrow aspirates. Furthermore, this interaction is disrupted by exposure to quisinostat, panobinostat, and HDTK-010. The identification of IRF4 as a putative binding partner for HDAC11 unveils a potential mechanism by which HDAC11 may regulate MM cell survival. Conclusions:We show that MM cell survival can be impaired by targeted inhibition of HDAC11. Furthermore, we identify IRF4 as a nuclear binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM cell survival. Disclosures Baz: Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Pinilla-Ibarz: ARIAD: Consultancy, Honoraria; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.
Fengdong Cheng - One of the best experts on this subject based on the ideXlab platform.
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HDAC11 regulates expression of c ebpβ and immunosuppressive molecules in myeloid derived suppressor cells
Journal of Leukocyte Biology, 2021Co-Authors: Jie Chen, Edward Seto, Eva Sahakian, John Powers, Fengdong Cheng, Jianguo Tao, Zi Wang, Javier Pinillaibarz, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells derived from bone marrow and negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previously we have demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increased suppressive activity against CD8+ T-cells. However, the mechanisms of HDAC11 that contribute to the suppressive function of MDSCs remain unclear. Here, we show that arginase activity and NO production is significantly higher in HDAC11 knockout MDSCs when compared with wild-type (WT) controls. In the absence of HDAC11, elevated arginase level and enzymatic activity were observed preferentially in the tumor-infiltrated granulocytic MDSCs, whereas iNOS expression and NO production were increased in the tumor-infiltrated monocytic MDSCs. Of note and for the first time, we demonstrated an association between the elevated expression of immunosuppressive molecules with up-regulation of the transcription factor C/EBPβ in MDSCs lacking HDAC11. Interestingly, the highest expression of C/EBPβ was observed among CD11b+ Gr-1+ MDSCs isolated from tumor-bearing mice. The additional demonstration that HDAC11 is recruited to the promoter region of C/EBPβ in WT MDSCs suggests a novel molecular mechanism by which HDAC11 influence the expression of immunosuppressive molecules in MDSCs through regulation of C/EBPβ gene expression.
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Loss of HDAC11 Promotes Myeloid-Derived Suppressor Cells Inhibition of T Cell Function in a Murine Lymphoma Microenvironment
Blood, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Michael Wang, Javier Pinilla Ibarz, Mitchell R. Smith, Eduardo M. SotomayorAbstract:Myeloid-derived suppressor cells constitute a heterogeneous population of immature myeloid cells derived from bone marrow that negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previous work in our lab had demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increase in suppressive activity against IFN-γ producing CD8+ T cells. The upregulated suppressive activity of HDAC11KO MDSCs was associated with a more aggressive tumor growth pattern when compared with wild type control mice. Mechanistically we have found that tumor infiltrated HDAC11KO MDSCs isolated from lymphoma-bearing mice displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function, when compare with wild type MDSCs. However, both arginase activity and NO production were at a similar level in the wild type and HDAC11KO MDSCs isolated from spleens of the same lymphoma-bearing mice. This finding suggests that HDAC11KO MDSCs are more suppressive within the tumor microenvironment. Moreover, the aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been previously shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of both MDSC and/or T-cells from either wild type or HDAC11 KO mice into C57BL/6 lymphoma-bearing animals. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the HDAC11KO T cells in the lymphoma microenvironment Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs phenotype and function in a murine lymphoma model. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells in vivo. Disclosures No relevant conflicts of interest to declare.
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loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model
Life Science Alliance, 2018Co-Authors: Lei Sun, Fengdong Cheng, Elphine Telles, Noreen Luetteke, Eduardo Sotomayor, Molly Karl, Robert H Miller, Edward SetoAbstract:Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). There is no known cure for MS, and currently available drugs for managing this disease are only effective early on and have many adverse side effects. Results from recent studies suggest that histone deacetylase (HDAC) inhibitors may be useful for the treatment of autoimmune and inflammatory diseases such as MS. However, the underlying mechanisms by which HDACs influence immune-mediated diseases such as MS are unclear. More importantly, the question of which specific HDAC(s) are suitable drug targets for the potential treatment of MS remains unanswered. Here, we investigate the functional role of HDAC11 in experimental autoimmune encephalomyelitis, a mouse model for MS. Our results indicate that the loss of HDAC11 in KO mice significantly reduces clinical severity and demyelination of the spinal cord in the post-acute phase of experimental autoimmune encephalomyelitis. The absence of HDAC11 leads to reduced immune cell infiltration into the CNS and decreased monocytes and myeloid DCs in the chronic progressive phase of the disease. Mechanistically, HDAC11 controls the expression of the pro-inflammatory chemokine C–C motif ligand 2 (CCL2) gene by enabling the binding of PU.1 transcription factor to the CCL2 promoter. Our results reveal a novel pathophysiological function for HDAC11 in CNS demyelinating diseases, and warrant further investigations into the potential use of HDAC11-specific inhibitors for the treatment of chronic progressive MS.
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abstract 4967 HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid derived suppressor cells transition
Cancer Research, 2018Co-Authors: Jie Chen, Eva Sahakian, John Powers, Fengdong Cheng, Alejandro Villagra, Zi Wang, Javier Pinillaibarz, Eduardo SotomayorAbstract:In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC9s in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells. Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells. Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4967.
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Essential role for histone deacetylase 11 (HDAC11) in neutrophil biology.
Journal of leukocyte biology, 2017Co-Authors: Eva Sahakian, John Powers, Jie Chen, Susan L Deng, Maritza Lienlaf, Hongwei Wang, Xianghong Chen, Kamira Maharaj, Alex Achille, Fengdong ChengAbstract:Epigenetic changes in chromatin structure have been recently associated with the deregulated expression of critical genes in normal and malignant processes. HDAC11, the newest member of the HDAC family of enzymes, functions as a negative regulator of IL-10 expression in APCs, as previously described by our lab. However, at the present time, its role in other hematopoietic cells, specifically in neutrophils, has not been fully explored. In this report, for the first time, we present a novel physiologic role for HDAC11 as a multifaceted regulator of neutrophils. Thus far, we have been able to demonstrate a lineage-restricted overexpression of HDAC11 in neutrophils and committed neutrophil precursors (promyelocytes). Additionally, we show that HDAC11 appears to associate with the transcription machinery, possibly regulating the expression of inflammatory and migratory genes in neutrophils. Given the prevalence of neutrophils in the peripheral circulation and their central role in the first line of defense, our results highlight a unique and novel role for HDAC11. With the consideration of the emergence of new, selective HDAC11 inhibitors, we believe that our findings will have significant implications in a wide range of diseases spanning malignancies, autoimmunity, and inflammation.
Mònica Suelves - One of the best experts on this subject based on the ideXlab platform.
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HDAC11 a multifaceted histone deacetylase with proficient fatty deacylase activity and its roles in physiological processes
FEBS Journal, 2021Co-Authors: Yaiza Nunezalvarez, Mònica SuelvesAbstract:The histone deacetylases (HDACs) family of enzymes possess deacylase activity for histone and nonhistone proteins; HDAC11 is the latest discovered HDAC and the only member of class IV. Besides its shared HDAC family catalytical activity, recent studies underline HDAC11 as a multifaceted enzyme with a very efficient long-chain fatty acid deacylase activity, which has open a whole new field of action for this protein. Here, we summarize the importance of HDAC11 in a vast array of cellular pathways, which has been recently highlighted by discoveries about its subcellular localization, biochemical features, and its regulation by microRNAs and long noncoding RNAs, as well as its new targets and interactors. Additionally, we discuss the recent work showing the consequences of HDAC11 dysregulation in brain, skeletal muscle, and adipose tissue, and during regeneration in response to kidney, skeletal muscle, and vascular injuries, underscoring HDAC11 as an emerging hub protein with physiological functions that are much more extensive than previously thought, and with important implications in human diseases.
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Loss of HDAC11 accelerates skeletal muscle regeneration in mice.
The FEBS journal, 2020Co-Authors: Yaiza Núñez-Álvarez, Erica Hurtado, Mar Muñoz, Alberto M. Pendás, Miguel A. Peinado, Ignacio García-tuñón, Gabriel E. Rech, Raquel Pluvinet, Lauro Sumoy, Mònica SuelvesAbstract:Histone deacetylase 11 (HDAC11) is the latest identified member of the histone deacetylase family of enzymes. It is highly expressed in brain, heart, testis, kidney, and skeletal muscle, although its role in these tissues is poorly understood. Here, we investigate for the first time the consequences of HDAC11 genetic impairment on skeletal muscle regeneration, a process principally dependent on its resident stem cells (satellite cells) in coordination with infiltrating immune cells and stromal cells. Our results show that HDAC11 is dispensable for adult muscle growth and establishment of the satellite cell population, while HDAC11 deficiency advances the regeneration process in response to muscle injury. This effect is not caused by differences in satellite cell activation or proliferation upon injury, but rather by an enhanced capacity of satellite cells to differentiate at early regeneration stages in the absence of HDAC11. Infiltrating HDAC11-deficient macrophages could also contribute to this accelerated muscle regenerative process by prematurely producing high levels of IL-10, a cytokine known to promote myoblast differentiation. Altogether, our results show that HDAC11 depletion advances skeletal muscle regeneration and this finding may have potential implications for designing new strategies for muscle pathologies coursing with chronic damage. DATABASE: Data were deposited in NCBI's Gene Expression Omnibus accessible through GEO Series accession number GSE147423.
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HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle.
The FEBS journal, 2020Co-Authors: Erica Hurtado, Yaiza Núñez-Álvarez, Mar Muñoz, Cristina Gutiérrez-caballero, Josefina Casas, Alberto M. Pendás, Miguel A. Peinado, Mònica SuelvesAbstract:Skeletal muscle is the largest tissue in mammalian organisms and is a key determinant of basal metabolic rate and whole-body energy metabolism. Histone deacetylase 11 (HDAC11) is the only member of the class IV subfamily of HDACs and it is highly expressed in skeletal muscle, but its role in skeletal muscle physiology has never been investigated. Here, we describe for the first time the consequences of HDAC11 genetic deficiency in skeletal muscle, which results in the improvement of muscle function enhancing fatigue resistance and muscle strength. Loss of HDAC11 had no obvious impact on skeletal muscle structure but increased the number of oxidative myofibers by promoting a glycolytic-to-oxidative muscle fiber switch. Unexpectedly, HDAC11 was localized in muscle mitochondria and its deficiency enhanced mitochondrial content. In particular, we showed that HDAC11 depletion increased mitochondrial fatty acid β-oxidation through activating the AMPK-ACC pathway and reducing acylcarnitine levels in vivo, thus providing a mechanistic explanation for the improved muscle strength and fatigue resistance. Overall, our data reveal a unique role of HDAC11 in the maintenance of muscle fiber-type balance and the mitochondrial lipid oxidation. These findings shed light on the mechanisms governing muscle metabolism and may have implications for chronic muscle metabolic diseases management.
