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Nidhi Bansal - One of the best experts on this subject based on the ideXlab platform.
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Targeted interference of SIN3A-TGIF1 function by SID decoy treatment inhibits Wnt signaling and invasion in triple negative breast cancer cells
Oncotarget, 2016Co-Authors: Yeonjin Kwon, Boris A Leibovitch, Nidhi Bansal, Eduardo F. Farias, Arthur Zelent, Chi Yeh Chung, Lutecia Pereira, Edgardo V. Ariztia, Samuel WaxmanAbstract:// Yeon-Jin Kwon 1 , Boris A. Leibovitch 1 , Nidhi Bansal 1 , Lutecia Pereira 2 , Chi-Yeh Chung 1 , Edgardo V. Ariztia 1 , Arthur Zelent 2 , Eduardo F. Farias 1 and Samuel Waxman 1 1 Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA 2 University of Miami, Sylvester Comprehensive Cancer Center, Florida MI, USA Correspondence to: Samuel Waxman, email: samuel.waxman@mssm.edu Eduardo F. Farias, email: eduardo.farias@mssm.edu Keywords: triple negative breast cancer, invasion, SIN3A, TGIF1, Wnt, metastasis Received: May 20, 2016 Accepted: July 23, 2016 Published: August 19, 2016 ABSTRACT Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poorer survival in triple negative breast cancer (TNBC) patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need in the treatment of cancer. We reported that the selective inhibition of the PAH2 domain of SIN3A protein function markedly suppressed metastatic dissemination to the lungs in TNBC xenograft bearing mice. Here, we show that TNBC cell lines treated with Sin3 interaction domain (SID) decoy peptides that bind to PAH2 display a strong in vitro inhibition of transwell invasion. This is accompanied by actin cytoskeleton reorganization with increased cortical actin deposition and downregulation of known Wnt target genes that are associated with epithelial to mesenchymal transition (EMT) and cancer cell invasion. Wnt pathway inhibition by SID decoy peptide was confirmed by decreased Wnt reporter activity and altered cytoplasmic localization of nuclear β-catenin. TGIF1, a transcription factor that modulates Wnt signaling and known to interact with the PAH2 domain of SIN3A, can be dissociated from the SIN3A complex by SID decoys. TGIF1 knockdown inhibits WNT target genes and in vitro cell invasion suggesting that TGIF1 might be a key target of the SID decoys to block tumor invasion. Taken together, targeting SIN3 function using SID decoys is a novel strategy to reverse invasion and the EMT program in TNBC translating into the inhibition of metastasis dissemination and eradication of residual disease.
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Blocking the PAH2 domain of SIN3A inhibits tumorigenesis and confers retinoid sensitivity in triple negative breast cancer
Oncotarget, 2016Co-Authors: Nidhi Bansal, Boris A Leibovitch, Lutecia Pereira, Almudena Bosch, Elena Cubedo, Keely Pierzchalski, Jace W. Jones, Melissa Fishel, Maureen A. KaneAbstract:// Nidhi Bansal 1 , Almudena Bosch 1, * , Boris Leibovitch 1, * , Lutecia Pereira 2 , Elena Cubedo 2 , Jianshi Yu 3 , Keely Pierzchalski 3 , Jace W. Jones 3 , Melissa Fishel 1 , Maureen Kane 3 , Arthur Zelent 2 , Samuel Waxman 1 , Eduardo Farias 1 1 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA 3 Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA * These authors contributed equally to this work Correspondence to: Samuel Waxman, email: Samuel.waxman@mssm.edu Eduardo Farias, email: Eduardo.farias@mssm.edu Keywords: SIN3A, SID decoys, triple negative breast cancer, retinoids, metastases Received: March 11, 2016 Accepted: May 05, 2016 Published: June 07, 2016 ABSTRACT Triple negative breast cancer (TNBC) frequently relapses locally, regionally or as systemic metastases. Development of targeted therapy that offers significant survival benefit in TNBC is an unmet clinical need. We have previously reported that blocking interactions between PAH2 domain of chromatin regulator SIN3A and the Sin3 interaction domain (SID) containing proteins by SID decoys result in EMT reversal, and re-expression of genes associated with differentiation. Here we report a novel and therapeutically relevant combinatorial use of SID decoys. SID decoys activate RARα/β pathways that are enhanced in combination with RARα-selective agonist AM80 to induce morphogenesis and inhibit tumorsphere formation. These findings correlate with inhibition of mammary hyperplasia and a significant increase in tumor-free survival in MMTV-Myc oncomice treated with a small molecule mimetic of SID (C16). Further, in two well-established mouse TNBC models we show that treatment with C16-AM80 combination has marked anti-tumor effects, prevents lung metastases and seeding of tumor cells to bone marrow. This correlated to a remarkable 100% increase in disease-free survival with a possibility of “cure” in mice bearing a TNBC-like tumor. Targeting SIN3A by C16 alone or in combination with AM80 may thus be a promising adjuvant therapy for treating or preventing metastatic TNBC.
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Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer
Oncotarget, 2015Co-Authors: Nidhi Bansal, Boris A Leibovitch, Rossitza Christova, Kevin Petrie, Chi Yeh Chung, Louise Howell, Veronica Gil, Yordan Sbirkov, Eunjee Lee, Joanna WexlerAbstract:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.
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targeting the SIN3A pf1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer
Oncotarget, 2015Co-Authors: Nidhi Bansal, Boris A Leibovitch, Rossitza Christova, Kevin Petrie, Chi Yeh Chung, Louise Howell, Veronica Gil, Yordan Sbirkov, Eunjee Lee, Joanna WexlerAbstract:// Nidhi Bansal 1 , Kevin Petrie 2 , Rossitza Christova 2,* , Chi-Yeh Chung 3,* , Boris A. Leibovitch 1 , Louise Howell 2 , Veronica Gil 2 , Yordan Sbirkov 2 , EunJee Lee 4 , Joanna Wexler 1 , Edgardo V. Ariztia 1 , Rajal Sharma 1 , Jun Zhu 4 , Emily Bernstein 5 , Ming-Ming Zhou 1 , Arthur Zelent 6 , Eduardo Farias 1 and Samuel Waxman 1 1 Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA 2 Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom 3 Department of Oncological Sciences, Department of Genetics and Genomic Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 4 Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, USA 5 Department of Oncological Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 6 Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Florida, USA * These authors have contributed equally to this work Correspondence to: Samuel Waxman, email: // Keywords : epigenetics, SIN3, PF1, triple negative breast cancer, cancer stem cells Received : July 17, 2015 Accepted : September 24, 2015 Published : October 09, 2015 Abstract Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo . In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo . These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.
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abstract 807 selamectin and ivermectin are small molecule inhibitors that interfere with SIN3A pah2 function and exert anti tumor activity in triple negative breast cancer
Cancer Research, 2014Co-Authors: Yeonjin Kwon, Boris A Leibovitch, Mihaly Mezei, Rossitza Christova, Rajal Sharma, Edgardo Aritzia, Nidhi Bansal, Lei Zeng, Shuai Yang, Mingming ZhouAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA INTRODUCTION: Sin3 is a complex scaffolding protein that participates in epigenetic regulation involved in a variety of biological processes, including chromatin remodeling, development, differentiation, cell cycle and survival. Paired Amphipathic domain 2 (PAH2) domain of Sin3 was shown to interact with Sin3 interacting domain (SID)-containing transcription factors, such as Mxd1, KLF10/11, and REST. Previously, we reported that SID transcripts and decoy peptides disrupt the interactions between Sin3-PAH2 domain and SID-containing transcription factors and induce epigenetic reprogramming in TNBC. RESULTS AND CONCLUSION: Here we show that fourteen SMIs mimicking SID decoys were identified by in silico computation from a chemical library composed of 115,000 compounds. We confirmed that selamectin and ivermectin are SID decoys using duo-link assays. Our NMR 15N-HSQC spectroscopy binding results further demonstrated ivermectin, which shares the same binding site as selamectin, directly interacted with PAH2. Moreover, selamectin inhibited Sin3 repression activity as measured by mammalian two-hybrid and in vitro GST pull-down assays. Notably, ivermectin was approved by Food and Drug Administration (FDA) to treat small animals and human. However, the anti-tumorigenic roles for these SMIs had not been investigated in TNBC in vitro and in vivo. Remarkably, these SMIs did not affect growth in 2-dimensional (2D) clonogenecity assay, but significantly suppressed growth in 3D matrigel and tumorsphere cultures. Moreover, selamectin significantly suppressed Myc mammary tumor growth in vivo more than 50 percent without any cytotoxicity. Selamectin and ivermectin induced re-expression of CDH1 and ESR1, restoring tamoxifen sensitivity. Treatment with these compounds inhibited in vitro invasion as measured by Boyden chamber in MCF7/ADR and MDA-MB-231 cells. Selamectin and ivermectin were shown to alleviate multidrug resistance and enhance doxorubicin and paclitaxel cytotoxicity in MCF7/ADR cells, which is unrelated to disruption of Sin3-PAH2. Based on further studies of the SIN3A complexes using selamectin and ivermectin, we seek to identify novel SMIs with better efficiency for targeting Sin3 complex and treating TNBCs in the future. Citation Format: Yeon-Jin Kwon, Boris A. Leibovitch, Lei Zeng, Mihaly Mezei, Rossitza Christova, Shuai Yang, Rajal Sharma, Edgardo Aritzia, nidhi bansal, Ming-Ming Zhou, Authur Zelent, Eduardo Farias, Samuel Waxman. Selamectin and ivermectin are small molecule inhibitors that interfere with SIN3A-PAH2 function and exert anti-tumor activity in triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2014-807
Joseph A. Fontana - One of the best experts on this subject based on the ideXlab platform.
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SHP and SIN3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis
Molecular cancer therapeutics, 2009Co-Authors: Lulu Farhana, Jan Hermen Dannenberg, Marcia I. Dawson, Joseph A. FontanaAbstract:We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the SIN3A complex. In this report, we delineated the role of SHP and the SIN3A complex in 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and SIN3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated nuclear factor-kappaB (NF-kappaB) activation, and 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or SIN3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC-mediated NF-kappaB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC-enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-kappaB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by SIN3A because ablation of SIN3A resulted in a decrease in SHP expression. Thus, SHP and SIN3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis.
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shp and SIN3A expression are essential for adamantyl substituted retinoid related molecule mediated nuclear factor κb activation c fos c jun expression and cellular apoptosis
Molecular Cancer Therapeutics, 2009Co-Authors: Lulu Farhana, Jan Hermen Dannenberg, Marcia I. Dawson, Joseph A. FontanaAbstract:We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the SIN3A complex. In this report, we delineated the role of SHP and the SIN3A complex in 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and SIN3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated nuclear factor-kappaB (NF-kappaB) activation, and 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or SIN3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC-mediated NF-kappaB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC-enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-kappaB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by SIN3A because ablation of SIN3A resulted in a decrease in SHP expression. Thus, SHP and SIN3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis.
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Abstract #1472: SHP and SIN3A expression are essential for adamantyl-substituted retinoid related molecules-mediated NF\#954;B activation, c-Fos/c-Jun expression and cellular apoptosis.
Cancer Research, 2009Co-Authors: Lulu Farhana, Marcia I. Dawson, Joseph A. FontanaAbstract:Adamantyl-substituted retinoid-related (ARR) molecules are potent inducers of apoptosis of malignant cells and are under clinical development. We previously found that the ARRs bind to the small heterodimer partner (SHP) as well as the SIN3A complex. In this report, we delineated the role of SHP and the SIN3A complex in the ARR 4-[3\#8217;-(1-adamantyl)-4\#8217;-hydroxyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and SIN3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated NF\#954;B activation as well 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or SIN3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. SHP and SIN3A knockdown and knockout significantly inhibited 3-Cl-AHPC mediated caspase-3 activation as well as 3-Cl-AHPC mediated generation of the active 17 kDa cleaved caspase-3 protein. We have previously shown that SHP binding of the ARR resulted in the enhanced binding of ARR-bound SHP to a SIN3A complex. We now found that utilizing nuclear extracts derived from SHP knockdown MDA-MB-468 and SHP knockout MEF cells that [5,5\#8217;-3H2] AHPN binding to nuclear extracts and a SIN3A complex was dependent on the presence of SHP. We found that 3-Cl-AHPC enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. Loss of SHP expression completely inhibited 3-Cl-AHPC induction of c-Jun and c-Fos expression in both SHP ablated MEF and SHP knockdown MDA-MB-468 cells. We have previously shown that 3-Cl-AHPC-mediated NF\#954;B activation is necessary for apoptosis induction. Knockout of SHP expression in MEF cells and knockdown of SHP expression in MDA-MB-468 cells resulted in inhibition of 3-Cl-AHPC-mediated NF\#312;B activation. Previous studieshave shown that the c-Fos promoter contains a consensus sequence for the NFkB p65 subunit and c-Fos promoter activity can be enhanced through p65 binding. We found that loss of SHP expression inhibited p65 binding to the c-Fos promoter in MDA-MB-468 cells as demonstrated by chromatin immunoprecipitation assays. In addition, SHP expression and the binding of the ARR/SHP complex to a SIN3A complex are required for modification of the complex. Exposure of MDA-MB-468 cells to 3-Cl-AHPC resulted in increased HSP90\#945; binding to the SIN3A complex. Loss of SHP expression inhibited 3-Cl-AHPC-medited increase in HSP90\#945; expression as well as 3-Cl-AHPC enhanced association of HSP90\#945; to the SIN3A complex. We have also found that SHP expression is dependent on SIN3A levels since ablation of SIN3A resulted in decreased SHP expression. Thus, SHP and SIN3A play an important role in ARR induction of cellular apoptosis. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1472.
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abstract 1472 shp and SIN3A expression are essential for adamantyl substituted retinoid related molecules mediated nf 954 b activation c fos c jun expression and cellular apoptosis
Cancer Research, 2009Co-Authors: Lulu Farhana, Marcia I. Dawson, Joseph A. FontanaAbstract:Adamantyl-substituted retinoid-related (ARR) molecules are potent inducers of apoptosis of malignant cells and are under clinical development. We previously found that the ARRs bind to the small heterodimer partner (SHP) as well as the SIN3A complex. In this report, we delineated the role of SHP and the SIN3A complex in the ARR 4-[3\#8217;-(1-adamantyl)-4\#8217;-hydroxyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and SIN3A expression in a number of cell types on 3-Cl-AHPC-mediated growth inhibition and apoptosis induction, 3-Cl-AHPC-mediated NF\#954;B activation as well 3-Cl-AHPC-mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or SIN3A expression, while blocking 3-Cl-AHPC-mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. SHP and SIN3A knockdown and knockout significantly inhibited 3-Cl-AHPC mediated caspase-3 activation as well as 3-Cl-AHPC mediated generation of the active 17 kDa cleaved caspase-3 protein. We have previously shown that SHP binding of the ARR resulted in the enhanced binding of ARR-bound SHP to a SIN3A complex. We now found that utilizing nuclear extracts derived from SHP knockdown MDA-MB-468 and SHP knockout MEF cells that [5,5\#8217;-3H2] AHPN binding to nuclear extracts and a SIN3A complex was dependent on the presence of SHP. We found that 3-Cl-AHPC enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC-mediated apoptosis. Loss of SHP expression completely inhibited 3-Cl-AHPC induction of c-Jun and c-Fos expression in both SHP ablated MEF and SHP knockdown MDA-MB-468 cells. We have previously shown that 3-Cl-AHPC-mediated NF\#954;B activation is necessary for apoptosis induction. Knockout of SHP expression in MEF cells and knockdown of SHP expression in MDA-MB-468 cells resulted in inhibition of 3-Cl-AHPC-mediated NF\#312;B activation. Previous studieshave shown that the c-Fos promoter contains a consensus sequence for the NFkB p65 subunit and c-Fos promoter activity can be enhanced through p65 binding. We found that loss of SHP expression inhibited p65 binding to the c-Fos promoter in MDA-MB-468 cells as demonstrated by chromatin immunoprecipitation assays. In addition, SHP expression and the binding of the ARR/SHP complex to a SIN3A complex are required for modification of the complex. Exposure of MDA-MB-468 cells to 3-Cl-AHPC resulted in increased HSP90\#945; binding to the SIN3A complex. Loss of SHP expression inhibited 3-Cl-AHPC-medited increase in HSP90\#945; expression as well as 3-Cl-AHPC enhanced association of HSP90\#945; to the SIN3A complex. We have also found that SHP expression is dependent on SIN3A levels since ablation of SIN3A resulted in decreased SHP expression. Thus, SHP and SIN3A play an important role in ARR induction of cellular apoptosis. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1472.
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Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the SIN3A Repressor
Cancer research, 2007Co-Authors: Lulu Farhana, Marcia I. Dawson, Li Wang, Mark Leid, David D. Moore, Gang Liu, Zeben Xia, Joseph A. FontanaAbstract:6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor with a corepressor complex that minimally contains SIN3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-SIN3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of SIN3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor.
Boris A Leibovitch - One of the best experts on this subject based on the ideXlab platform.
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Targeted interference of SIN3A-TGIF1 function by SID decoy treatment inhibits Wnt signaling and invasion in triple negative breast cancer cells
Oncotarget, 2016Co-Authors: Yeonjin Kwon, Boris A Leibovitch, Nidhi Bansal, Eduardo F. Farias, Arthur Zelent, Chi Yeh Chung, Lutecia Pereira, Edgardo V. Ariztia, Samuel WaxmanAbstract:// Yeon-Jin Kwon 1 , Boris A. Leibovitch 1 , Nidhi Bansal 1 , Lutecia Pereira 2 , Chi-Yeh Chung 1 , Edgardo V. Ariztia 1 , Arthur Zelent 2 , Eduardo F. Farias 1 and Samuel Waxman 1 1 Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA 2 University of Miami, Sylvester Comprehensive Cancer Center, Florida MI, USA Correspondence to: Samuel Waxman, email: samuel.waxman@mssm.edu Eduardo F. Farias, email: eduardo.farias@mssm.edu Keywords: triple negative breast cancer, invasion, SIN3A, TGIF1, Wnt, metastasis Received: May 20, 2016 Accepted: July 23, 2016 Published: August 19, 2016 ABSTRACT Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poorer survival in triple negative breast cancer (TNBC) patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need in the treatment of cancer. We reported that the selective inhibition of the PAH2 domain of SIN3A protein function markedly suppressed metastatic dissemination to the lungs in TNBC xenograft bearing mice. Here, we show that TNBC cell lines treated with Sin3 interaction domain (SID) decoy peptides that bind to PAH2 display a strong in vitro inhibition of transwell invasion. This is accompanied by actin cytoskeleton reorganization with increased cortical actin deposition and downregulation of known Wnt target genes that are associated with epithelial to mesenchymal transition (EMT) and cancer cell invasion. Wnt pathway inhibition by SID decoy peptide was confirmed by decreased Wnt reporter activity and altered cytoplasmic localization of nuclear β-catenin. TGIF1, a transcription factor that modulates Wnt signaling and known to interact with the PAH2 domain of SIN3A, can be dissociated from the SIN3A complex by SID decoys. TGIF1 knockdown inhibits WNT target genes and in vitro cell invasion suggesting that TGIF1 might be a key target of the SID decoys to block tumor invasion. Taken together, targeting SIN3 function using SID decoys is a novel strategy to reverse invasion and the EMT program in TNBC translating into the inhibition of metastasis dissemination and eradication of residual disease.
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Blocking the PAH2 domain of SIN3A inhibits tumorigenesis and confers retinoid sensitivity in triple negative breast cancer
Oncotarget, 2016Co-Authors: Nidhi Bansal, Boris A Leibovitch, Lutecia Pereira, Almudena Bosch, Elena Cubedo, Keely Pierzchalski, Jace W. Jones, Melissa Fishel, Maureen A. KaneAbstract:// Nidhi Bansal 1 , Almudena Bosch 1, * , Boris Leibovitch 1, * , Lutecia Pereira 2 , Elena Cubedo 2 , Jianshi Yu 3 , Keely Pierzchalski 3 , Jace W. Jones 3 , Melissa Fishel 1 , Maureen Kane 3 , Arthur Zelent 2 , Samuel Waxman 1 , Eduardo Farias 1 1 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA 3 Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA * These authors contributed equally to this work Correspondence to: Samuel Waxman, email: Samuel.waxman@mssm.edu Eduardo Farias, email: Eduardo.farias@mssm.edu Keywords: SIN3A, SID decoys, triple negative breast cancer, retinoids, metastases Received: March 11, 2016 Accepted: May 05, 2016 Published: June 07, 2016 ABSTRACT Triple negative breast cancer (TNBC) frequently relapses locally, regionally or as systemic metastases. Development of targeted therapy that offers significant survival benefit in TNBC is an unmet clinical need. We have previously reported that blocking interactions between PAH2 domain of chromatin regulator SIN3A and the Sin3 interaction domain (SID) containing proteins by SID decoys result in EMT reversal, and re-expression of genes associated with differentiation. Here we report a novel and therapeutically relevant combinatorial use of SID decoys. SID decoys activate RARα/β pathways that are enhanced in combination with RARα-selective agonist AM80 to induce morphogenesis and inhibit tumorsphere formation. These findings correlate with inhibition of mammary hyperplasia and a significant increase in tumor-free survival in MMTV-Myc oncomice treated with a small molecule mimetic of SID (C16). Further, in two well-established mouse TNBC models we show that treatment with C16-AM80 combination has marked anti-tumor effects, prevents lung metastases and seeding of tumor cells to bone marrow. This correlated to a remarkable 100% increase in disease-free survival with a possibility of “cure” in mice bearing a TNBC-like tumor. Targeting SIN3A by C16 alone or in combination with AM80 may thus be a promising adjuvant therapy for treating or preventing metastatic TNBC.
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Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer
Oncotarget, 2015Co-Authors: Nidhi Bansal, Boris A Leibovitch, Rossitza Christova, Kevin Petrie, Chi Yeh Chung, Louise Howell, Veronica Gil, Yordan Sbirkov, Eunjee Lee, Joanna WexlerAbstract:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.
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targeting the SIN3A pf1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer
Oncotarget, 2015Co-Authors: Nidhi Bansal, Boris A Leibovitch, Rossitza Christova, Kevin Petrie, Chi Yeh Chung, Louise Howell, Veronica Gil, Yordan Sbirkov, Eunjee Lee, Joanna WexlerAbstract:// Nidhi Bansal 1 , Kevin Petrie 2 , Rossitza Christova 2,* , Chi-Yeh Chung 3,* , Boris A. Leibovitch 1 , Louise Howell 2 , Veronica Gil 2 , Yordan Sbirkov 2 , EunJee Lee 4 , Joanna Wexler 1 , Edgardo V. Ariztia 1 , Rajal Sharma 1 , Jun Zhu 4 , Emily Bernstein 5 , Ming-Ming Zhou 1 , Arthur Zelent 6 , Eduardo Farias 1 and Samuel Waxman 1 1 Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA 2 Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom 3 Department of Oncological Sciences, Department of Genetics and Genomic Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 4 Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, USA 5 Department of Oncological Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 6 Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Florida, USA * These authors have contributed equally to this work Correspondence to: Samuel Waxman, email: // Keywords : epigenetics, SIN3, PF1, triple negative breast cancer, cancer stem cells Received : July 17, 2015 Accepted : September 24, 2015 Published : October 09, 2015 Abstract Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo . In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo . These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.
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abstract 807 selamectin and ivermectin are small molecule inhibitors that interfere with SIN3A pah2 function and exert anti tumor activity in triple negative breast cancer
Cancer Research, 2014Co-Authors: Yeonjin Kwon, Boris A Leibovitch, Mihaly Mezei, Rossitza Christova, Rajal Sharma, Edgardo Aritzia, Nidhi Bansal, Lei Zeng, Shuai Yang, Mingming ZhouAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA INTRODUCTION: Sin3 is a complex scaffolding protein that participates in epigenetic regulation involved in a variety of biological processes, including chromatin remodeling, development, differentiation, cell cycle and survival. Paired Amphipathic domain 2 (PAH2) domain of Sin3 was shown to interact with Sin3 interacting domain (SID)-containing transcription factors, such as Mxd1, KLF10/11, and REST. Previously, we reported that SID transcripts and decoy peptides disrupt the interactions between Sin3-PAH2 domain and SID-containing transcription factors and induce epigenetic reprogramming in TNBC. RESULTS AND CONCLUSION: Here we show that fourteen SMIs mimicking SID decoys were identified by in silico computation from a chemical library composed of 115,000 compounds. We confirmed that selamectin and ivermectin are SID decoys using duo-link assays. Our NMR 15N-HSQC spectroscopy binding results further demonstrated ivermectin, which shares the same binding site as selamectin, directly interacted with PAH2. Moreover, selamectin inhibited Sin3 repression activity as measured by mammalian two-hybrid and in vitro GST pull-down assays. Notably, ivermectin was approved by Food and Drug Administration (FDA) to treat small animals and human. However, the anti-tumorigenic roles for these SMIs had not been investigated in TNBC in vitro and in vivo. Remarkably, these SMIs did not affect growth in 2-dimensional (2D) clonogenecity assay, but significantly suppressed growth in 3D matrigel and tumorsphere cultures. Moreover, selamectin significantly suppressed Myc mammary tumor growth in vivo more than 50 percent without any cytotoxicity. Selamectin and ivermectin induced re-expression of CDH1 and ESR1, restoring tamoxifen sensitivity. Treatment with these compounds inhibited in vitro invasion as measured by Boyden chamber in MCF7/ADR and MDA-MB-231 cells. Selamectin and ivermectin were shown to alleviate multidrug resistance and enhance doxorubicin and paclitaxel cytotoxicity in MCF7/ADR cells, which is unrelated to disruption of Sin3-PAH2. Based on further studies of the SIN3A complexes using selamectin and ivermectin, we seek to identify novel SMIs with better efficiency for targeting Sin3 complex and treating TNBCs in the future. Citation Format: Yeon-Jin Kwon, Boris A. Leibovitch, Lei Zeng, Mihaly Mezei, Rossitza Christova, Shuai Yang, Rajal Sharma, Edgardo Aritzia, nidhi bansal, Ming-Ming Zhou, Authur Zelent, Eduardo Farias, Samuel Waxman. Selamectin and ivermectin are small molecule inhibitors that interfere with SIN3A-PAH2 function and exert anti-tumor activity in triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2014-807
Gregory David - One of the best experts on this subject based on the ideXlab platform.
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Coregulator SIN3A Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca2+ Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response.
Diabetes, 2020Co-Authors: Xiaodun Yang, Sarah M. Graff, Cody N. Heiser, Bob Chen, Alan J. Simmons, Austin N. Southard-smith, Gregory David, David A. Jacobson, Irina KaverinaAbstract:Swi-independent 3a and 3b (SIN3A and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse SIN3A and Sin3b are coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of SIN3A in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca2+ influx of SIN3A-deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by SIN3A in β-cells, which modulate Ca2+/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both SIN3A and Sin3b in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed "general" coregulators SIN3A and Sin3b in islet β-cells, with SIN3A being dispensable for differentiation but required for postnatal function and survival.
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Coregulator SIN3A promotes postnatal murine β-cell fitness by regulating genes in Ca2+ homeostasis, cell survival, vesicle biosynthesis, glucose metabolism, and stress response
2020Co-Authors: Ada Admin, Xiaodun Yang, Sarah M. Graff, Cody N. Heiser, Bob Chen, Alan J. Simmons, Austin N. Southard-smith, Gregory David, David A. JacobsonAbstract:Swi-independent 3a and 3b (SIN3A and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse SIN3A and Sin3b are co-produced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine-cell function. Mice with loss of <i>SIN3A</i> in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca<sup>2+</sup> influx of <i>SIN3A</i>-deficient β-cells. RNA-seq coupled with candidate chromatin-immunoprecipitation assays revealed several genes that could be directly regulated by SIN3A in β-cells, which modulate Ca<sup>2+</sup>/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Lastly, mice with loss of both <i>SIN3A</i> and <i>Sin3b</i> in multipotent embryonic pancreatic progenitors had significantly reduced islet-cell mass at birth, caused by decreased endocrine-progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed “general” coregulators SIN3A and Sin3b in islet β-cells, with SIN3A being dispensable for differentiation but required for postnatal function and survival.
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SIN3A regulates epithelial progenitor cell fate during lung development.
Development (Cambridge England), 2017Co-Authors: Changfu Yao, Gregory David, Gianni Carraro, Bindu Konda, Xiangrong Guan, Takako Mizuno, Norika Chiba, Matthew Kostelny, Adrianne Kurkciyan, Jonathan L. McqualterAbstract:Mechanisms that regulate tissue-specific progenitors for maintenance and differentiation during development are poorly understood. Here, we demonstrate that the co-repressor protein SIN3A is crucial for lung endoderm development. Loss of SIN3A in mouse early foregut endoderm led to a specific and profound defect in lung development with lung buds failing to undergo branching morphogenesis and progressive atrophy of the proximal lung endoderm with complete epithelial loss at later stages of development. Consequently, neonatal pups died at birth due to respiratory insufficiency. Further analysis revealed that loss of SIN3A resulted in embryonic lung epithelial progenitor cells adopting a senescence-like state with permanent cell cycle arrest in G1 phase. This was mediated at least partially through upregulation of the cell cycle inhibitors Cdkn1a and Cdkn2c. At the same time, loss of endodermal SIN3A also disrupted cell differentiation of the mesoderm, suggesting aberrant epithelial-mesenchymal signaling. Together, these findings reveal that SIN3A is an essential regulator for early lung endoderm specification and differentiation.
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Chromatin associated SIN3A is essential for male germ cell lineage in the mouse
Developmental biology, 2012Co-Authors: Jessica Pellegrino, Diego H. Castrillon, Gregory DavidAbstract:Spermatogenesis is a complex process that requires coordinated proliferation and differentiation of male germ cells. The molecular events that dictate this process are largely unknown, but are likely to involve highly regulated transcriptional control. In this study, we investigate the contribution of chromatin associated SIN3A in mouse germ cell lineage development. Genetic inactivation of SIN3A in the male germline leads to sterility that results from the early and penetrant apoptotic death observed in SIN3A-deleted germ cells, coincident with the reentry in mitosis. SIN3A-deleted testes exhibit a Sertoli-cell only phenotype, consistent with the absolute requirement for SIN3A in germ cells' development and/or viability. Interestingly, transcripts analysis revealed that the expression program of Sertoli cells is altered upon inactivation of SIN3A in germ cells. These studies identified a central role for the mammalian Sin3-HDAC complex in the germ cell lineage, and point to an exquisite transcriptional crosstalk between germ cells and their niche to support fertility in mammals.
Cheng-fu Kao - One of the best experts on this subject based on the ideXlab platform.
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Interplay between SIN3A and STAT3 mediates chromatin conformational changes and GFAP expression during cellular differentiation.
PloS one, 2011Co-Authors: Pei-yi Cheng, Yu-ping Lin, Ya-ling Chen, Yi-ching Lee, Chia-chen Tai, Yi-ting Wang, Yu-ju Chen, Cheng-fu KaoAbstract:Neurons and astrocytes are generated from common neural precursors, yet neurogenesis precedes astrocyte formation during embryogenesis. The mechanisms of neural development underlying suppression and de-suppression of differentiation-related genes for cell fate specifications are not well understood. By using an in vitro system in which NTera-2 cells were induced to differentiate into an astrocyte-like lineage, we revealed a novel role for SIN3A in maintaining the suppression of GFAP in NTera-2 cells. SIN3A coupled with MeCP2 bound to the GFAP promoter and their occupancies were correlated with repression of GFAP transcription. The repression by SIN3A and MeCP2 may be an essential mechanism underlying the inhibition of cell differentiation. Upon commitment toward an astrocyte-like lineage, SIN3A- MeCP2 departed from the promoter and activated STAT3 simultaneously bound to the promoter and exon 1 of GFAP; meanwhile, olig2 was exported from nuclei to the cytoplasm. This suggested that a three-dimensional or higher-order structure was provoked by STAT3 binding between the promoter and proximal coding regions. STAT3 then recruited CBP/p300 to exon 1 and targeted the promoter for histone H3K9 and H3K14 acetylation. The CBP/p300-mediated histone modification further facilitates chromatin remodeling, thereby enhancing H3K4 trimethylation and recruitment of RNA polymerase II to activate GFAP gene transcription. These results provide evidence that exchange of repressor and activator complexes and epigenetic modifications are critical strategies for cellular differentiation and lineage-specific gene expression.
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interplay between SIN3A and stat3 mediates chromatin conformational changes and gfap expression during cellular differentiation
PLOS ONE, 2011Co-Authors: Pei-yi Cheng, Yu-ping Lin, Ya-ling Chen, Yi-ching Lee, Chia-chen Tai, Yi-ting Wang, Yu-ju Chen, Cheng-fu KaoAbstract:Background: Neurons and astrocytes are generated from common neural precursors, yet neurogenesis precedes astrocyte formation during embryogenesis. The mechanisms of neural development underlying suppression and de-suppression of differentiation- related genes for cell fate specifications are not well understood. Methodology/Principal Findings: By using an in vitro system in which NTera-2 cells were induced to differentiate into an astrocyte-like lineage, we revealed a novel role for SIN3A in maintaining the suppression of GFAP in NTera-2 cells. SIN3A coupled with MeCP2 bound to the GFAP promoter and their occupancies were correlated with repression of GFAP transcription. The repression by SIN3A and MeCP2 may be an essential mechanism underlying the inhibition of cell differentiation. Upon commitment toward an astrocyte-like lineage, SIN3A- MeCP2 departed from the promoter and activated STAT3 simultaneously bound to the promoter and exon 1 of GFAP; meanwhile, olig2 was exported from nuclei to the cytoplasm. This suggested that a three-dimensional or higher-order structure was provoked by STAT3 binding between the promoter and proximal coding regions. STAT3 then recruited CBP/p300 to exon 1 and targeted the promoter for histone H3K9 and H3K14 acetylation. The CBP/p300-mediated histone modification further facilitates chromatin remodeling, thereby enhancing H3K4 trimethylation and recruitment of RNA polymerase II to activate GFAP gene transcription. Conclusions/Significance: These results provide evidence that exchange of repressor and activator complexes and epigenetic modifications are critical strategies for cellular differentiation and lineage-specific gene expression.