The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Christian Bronner - One of the best experts on this subject based on the ideXlab platform.
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targeting microrna UHRF1 pathways as a novel strategy for cancer therapy review
Oncology Letters, 2017Co-Authors: Hani Choudhry, Christian Bronner, Marc Mousli, Ziad Omran, Mazin A Zamzami, Mahmoud AlhosinAbstract:Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat-interacting protein 60 and histone methyltransferases G9a and Suv39H1. UHRF1 is considered to control a large macromolecular protein complex termed epigenetic code replication machinery, in order to maintain epigenetic silencing of TSGs during cell division, thus enabling cancer cells to escape apoptosis. MicroRNAs (miRNAs) are able to regulate the expression of its target gene by functioning as either an oncogene or a tumor suppressor. In the present review, the role of tumor suppressive miRNAs in the regulation of UHRF1, and the importance of targeting the microRNA/UHRF1 pathways in order to induce the reactivation of silenced TSGs and subsequent apoptosis are discussed.
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signalling pathways in UHRF1 dependent regulation of tumor suppressor genes in cancer
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Mahmoud Alhosin, Marc Mousli, Ziad Omran, Mazin A Zamzami, Abdulrahman L Almalki, Hani Choudhry, Christian BronnerAbstract:Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.
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Tandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation
European Journal of Medicinal Chemistry, 2016Co-Authors: Vassilios Myrianthopoulos, Pierre-francois Cartron, Zita Liutkeviciute, Saulius Klimasauskas, Daumantas Matulis, Christian Bronner, Nadine Martinet, Emmanuel MikrosAbstract:Ubiquitin-like protein UHRF1 that contains PHD and RING finger domain 1 is a key epigenetic protein enabling maintenance of the DNA methylation status through replication. A tandem virtual screening approach was implemented for identifying small molecules able to bind the 5-methylcytosine pocket of UHRF1 and inhibit its functionality. The NCI/DTP small molecules Repository was screened in silico by a combined protocol implementing structure-based and ligand-based methodologies. Consensus ranking was utilized to select a set of 27 top-ranked compounds that were subsequently evaluated experimentally in a stepwise manner for their ability to demethylate DNA in cellulo using PCR-MS and HPLC-MS/MS. The most active molecules were further assessed in a cell-based setting by the Proximity Ligation In Situ Assay and the ApoTome technology. Both evaluations confirmed that the DNMT1/UHRF1 interactions were significantly reduced after 4 h of incubation of U251 glioma cells with the most potent compound NSC232003, showing a 50% interaction inhibition at 15 mM as well as induction of global DNA cytosine demethylation as measured by ELISA. This is the first report of a chemical tool that targets UHRF1 and modulates DNA methylation in a cell context by potentially disrupting DNMT1/UHRF1 interactions. Compound NSC232003, a uracil derivative freely available by the NCI/DTP Repository, provides a versatile lead for developing highly potent and cell-permeable UHRF1 inhibitors that will enable dissection of DNA methylation inheritance.
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cd47 activation induced UHRF1 over expression is associated with silencing of tumor suppressor gene p16ink4a in glioblastoma cells
Anticancer Research, 2015Co-Authors: Abdelaziz Boukhari, Christian Bronner, Valerie B Schinikerth, Mahmoud Alhosin, Krizia Sagini, Cecile Truchot, Emilie Sick, Philippe Andre, Yves Mely, Marc MousliAbstract:CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
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increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis
Biochemical Pharmacology, 2013Co-Authors: Christian Bronner, Mounira Krifa, Marc MousliAbstract:Epigenetic mechanisms such as DNA methylation and histone posttranslational modifications, allow cells to maintain the phenotype throughout successive mitosis. UHRF1 plays a major role in the inheritance of some epigenetic marks from mother cells to daughter cells due to its particular structural domains. The originality of UHRF1 lies in the fact that it can read epigenetic marks and recruit the enzymes that catalyze the same epigenetic mark. The SRA domain senses the presence of a methylated cytosine on one DNA strand allowing the recruitment of DNMT1, which methylates the cytosine on the newly synthesized DNA. The recently identified tudor domain of UHRF1 senses the presence of methylated histone H3 conducting UHRF1 to recruit histone methyltransferases. Recent studies deciphering the relationships between some of the structural domains of UHRF1 provides new insights on the reading of the epigenetic code over a larger portion of histone tail than usually expected. Furthermore, latest developments highlights that UHRF1 is one of the proteins which is able to directly connect DNA methylation to histone epigenetic marks. This paper reviews the principles how UHRF1 acts as an epigenetic reader and discusses the properties of UHRF1 to be a biomarker as well as a therapeutic target.
Marc Mousli - One of the best experts on this subject based on the ideXlab platform.
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targeting microrna UHRF1 pathways as a novel strategy for cancer therapy review
Oncology Letters, 2017Co-Authors: Hani Choudhry, Christian Bronner, Marc Mousli, Ziad Omran, Mazin A Zamzami, Mahmoud AlhosinAbstract:Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat-interacting protein 60 and histone methyltransferases G9a and Suv39H1. UHRF1 is considered to control a large macromolecular protein complex termed epigenetic code replication machinery, in order to maintain epigenetic silencing of TSGs during cell division, thus enabling cancer cells to escape apoptosis. MicroRNAs (miRNAs) are able to regulate the expression of its target gene by functioning as either an oncogene or a tumor suppressor. In the present review, the role of tumor suppressive miRNAs in the regulation of UHRF1, and the importance of targeting the microRNA/UHRF1 pathways in order to induce the reactivation of silenced TSGs and subsequent apoptosis are discussed.
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signalling pathways in UHRF1 dependent regulation of tumor suppressor genes in cancer
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Mahmoud Alhosin, Marc Mousli, Ziad Omran, Mazin A Zamzami, Abdulrahman L Almalki, Hani Choudhry, Christian BronnerAbstract:Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.
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cd47 activation induced UHRF1 over expression is associated with silencing of tumor suppressor gene p16ink4a in glioblastoma cells
Anticancer Research, 2015Co-Authors: Abdelaziz Boukhari, Christian Bronner, Valerie B Schinikerth, Mahmoud Alhosin, Krizia Sagini, Cecile Truchot, Emilie Sick, Philippe Andre, Yves Mely, Marc MousliAbstract:CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
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increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis
Biochemical Pharmacology, 2013Co-Authors: Christian Bronner, Mounira Krifa, Marc MousliAbstract:Epigenetic mechanisms such as DNA methylation and histone posttranslational modifications, allow cells to maintain the phenotype throughout successive mitosis. UHRF1 plays a major role in the inheritance of some epigenetic marks from mother cells to daughter cells due to its particular structural domains. The originality of UHRF1 lies in the fact that it can read epigenetic marks and recruit the enzymes that catalyze the same epigenetic mark. The SRA domain senses the presence of a methylated cytosine on one DNA strand allowing the recruitment of DNMT1, which methylates the cytosine on the newly synthesized DNA. The recently identified tudor domain of UHRF1 senses the presence of methylated histone H3 conducting UHRF1 to recruit histone methyltransferases. Recent studies deciphering the relationships between some of the structural domains of UHRF1 provides new insights on the reading of the epigenetic code over a larger portion of histone tail than usually expected. Furthermore, latest developments highlights that UHRF1 is one of the proteins which is able to directly connect DNA methylation to histone epigenetic marks. This paper reviews the principles how UHRF1 acts as an epigenetic reader and discusses the properties of UHRF1 to be a biomarker as well as a therapeutic target.
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epigallocatechin 3 gallate up regulates tumor suppressor gene expression via a reactive oxygen species dependent down regulation of UHRF1
Biochemical and Biophysical Research Communications, 2012Co-Authors: Mayada Achour, Valerie B Schinikerth, Mahmoud Alhosin, Marc Mousli, Abdulkhaleg Ibrahim, Jean Peluso, Christian D Muller, Ali Hamiche, Sirano Dhepaganon, Christian BronnerAbstract:Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) contributes to silencing of tumor suppressor genes by recruiting DNA methyltransferase 1 (DNMT1) to their hemi-methylated promoters. Conversely, demethylation of these promoters has been ascribed to the natural anti-cancer drug, epigallocatechin-3-gallate (EGCG). The aim of the present study was to investigate whether the UHRF1/DNMT1 pair is an important target of EGCG action. Here, we show that EGCG down-regulates UHRF1 and DNMT1 expression in Jurkat cells, with subsequent up-regulation of p73 and p16(INK4A) genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16(INK4A) is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16(INK4A) and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16(INK4A) and p73, either in the presence or absence of EGCG. Our results show that down-regulation of UHRF1 is upstream to many cellular events, including G1 cell arrest, up-regulation of tumor suppressor genes and apoptosis.
Jiemin Wong - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Ubiquitin-like with Plant Homeodomain and RING Finger Domain 1 (UHRF1) Protein Stability by Heat Shock Protein 90 Chaperone Machinery.
The Journal of biological chemistry, 2016Co-Authors: Guangjin Ding, Peilin Chen, Hui Zhang, Xiaojie Huang, Yi Zang, Jiemin WongAbstract:As a protein critical for DNA maintenance methylation and cell proliferation, UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy. In a high throughput screening for small molecules that induce UHRF1 protein degradation, we have identified the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). We present evidence that UHRF1 interacts with HSP90 chaperone complex and is a novel HSP90 client protein. Pharmacological inhibition of HSP90 with 17-AAG or 17-dimethylaminoethylamino-17-demethoxygeldanamycin results in UHRF1 ubiquitination and proteasome-dependent degradation. Interestingly, this HSP90 inhibitor-induced UHRF1 degradation is independent of CHIP and CUL5, two previously identified ubiquitin E3 ligases for HSP90 client proteins. In addition, this degradation is dependent neither on the intrinsic E3 ligase of UHRF1 nor on the E3 ligase SCF(β-TRCP) that has been implicated in regulation of UHRF1 stability. We also provide evidence that HSP90 inhibitors may suppress cancer cell proliferation in part through its induced UHRF1 degradation. Taken together, our results identify UHRF1 as a novel HSP90 client protein and shed light on the regulation of UHRF1 stability and function.
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non germ line restoration of genomic imprinting for a small subset of imprinted genes in ubiquitin like phd and ring finger domain containing 1 UHRF1 null mouse embryonic stem cells
Journal of Biological Chemistry, 2015Co-Authors: Zhiqiang Wang, Tieliu Shi, Jiemin WongAbstract:The underlying mechanism for the establishment and maintenance of differential DNA methylation in imprinted genes is largely unknown. Previous studies using Dnmt1 knock-out embryonic stem (ES) cells demonstrated that, although re-expression of DNMT1 restored DNA methylation in the non-imprinted regions, the methylation patterns of imprinted genes could be restored only through germ line passage. Knock-out of UHRF1, an accessory factor essential for DNMT1-mediated DNA methylation, in mouse ES cells also led to impaired global DNA methylation and loss of genomic imprinting. Here, we demonstrate that, although re-expression of UHRF1 in UHRF1(-/-) ES cells restored DNA methylation for the bulk genome but not for most of the imprinted genes, it did rescue DNA methylation for the imprinted H19, Nnat, and Dlk1 genes. Analysis of histone modifications at the differential methylated regions of the imprinted genes by ChIP assays revealed that for the imprinted genes whose DNA methylation could be restored upon re-expression of UHRF1, the active histone markers (especially H3K4me3) were maintained at considerably low levels, and low levels were maintained even in UHRF1(-/-) ES cells. In contrast, for the imprinted genes whose DNA methylation could not be restored upon UHRF1 re-expression, the active histone markers (especially H3K4me3) were relatively high and became even higher in UHRF1(-/-) ES cells. Our study thus supports a role for histone modifications in determining the establishment of imprinting-related DNA methylation and demonstrates that mouse ES cells can be a valuable model for mechanistic study of the establishment and maintenance of differential DNA methylation in imprinted genes.
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UHRF1 targets dnmt1 for dna methylation through cooperative binding of hemi methylated dna and methylated h3k9
Nature Communications, 2013Co-Authors: Xiaoli Liu, Jiqin Zhang, Qinqin Gao, Haruhiko Koseki, Qian Zhao, Jiemin WongAbstract:Epigenetic inheritance of DNA methylation requires the recruitment of DNA methyltransferase activity to the replication fork by UHRF1. Liu et al. show that optimal association of UHRF1 with the replication fork and resulting DNA methylation requires two domains that bind hemi-methylated DNA and methylated histones, respectively.
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s phase dependent interaction with dnmt1 dictates the role of UHRF1 but not uhrf2 in dna methylation maintenance
Cell Research, 2011Co-Authors: Jiqin Zhang, Qinqin Gao, Xiaoli Liu, Yuanhui Jia, Shuo Dong, Haruhiko Koseki, Jiemin WongAbstract:Recent studies demonstrate that UHRF1 is required for DNA methylation maintenance by targeting DNMT1 to DNA replication foci, presumably through its unique hemi-methylated DNA-binding activity and interaction with DNMT1. UHRF2, another member of the UHRF family proteins, is highly similar to UHRF1 in both sequence and structure, raising questions about its role in DNA methylation. In this study, we demonstrate that, like UHRF1, UHRF2 also binds preferentially to methylated histone H3 lysine 9 (H3K9) through its conserved tudor domain and hemi-methylated DNA through the SET and Ring associated domain. Like UHRF1, UHRF2 is enriched in pericentric heterochromatin. The heterochromatin localization depends to large extent on its methylated H3K9-binding activity and to less extent on its methylated DNA-binding activity. Coimmunoprecipitation experiments demonstrate that both UHRF1 and UHRF2 interact with DNMT1, DNMT3a, DNMT3b and G9a. Despite all these conserved functions, we find that UHRF2 is not able to rescue the DNA methylation defect in UHRF1 null mouse embryonic stem cells. This can be attributed to the inability for UHRF2 to recruit DNMT1 to replication foci during S phase of the cell cycle. Indeed, we find that while UHRF1 interacts with DNMT1 in an S phase-dependent manner in cells, UHRF2 does not. Thus, our study demonstrates that UHRF2 and UHRF1 are not functionally redundant in DNA methylation maintenance and reveals the cell-cycle-dependent interaction between UHRF1 and DNMT1 as a key regulatory mechanism targeting DNMT1 for DNA methylation.
Mahmoud Alhosin - One of the best experts on this subject based on the ideXlab platform.
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targeting microrna UHRF1 pathways as a novel strategy for cancer therapy review
Oncology Letters, 2017Co-Authors: Hani Choudhry, Christian Bronner, Marc Mousli, Ziad Omran, Mazin A Zamzami, Mahmoud AlhosinAbstract:Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms. UHRF1 overexpression is observed in a number of solid tumors and hematological malignancies, and is considered a primary mechanism in inhibiting apoptosis. UHRF1 exerts its inhibitory activity on TSGs by binding to functional domains and therefore influences several epigenetic actors including DNA methyltransferase, histone deacetylase 1, histone acetyltransferase Tat-interacting protein 60 and histone methyltransferases G9a and Suv39H1. UHRF1 is considered to control a large macromolecular protein complex termed epigenetic code replication machinery, in order to maintain epigenetic silencing of TSGs during cell division, thus enabling cancer cells to escape apoptosis. MicroRNAs (miRNAs) are able to regulate the expression of its target gene by functioning as either an oncogene or a tumor suppressor. In the present review, the role of tumor suppressive miRNAs in the regulation of UHRF1, and the importance of targeting the microRNA/UHRF1 pathways in order to induce the reactivation of silenced TSGs and subsequent apoptosis are discussed.
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signalling pathways in UHRF1 dependent regulation of tumor suppressor genes in cancer
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Mahmoud Alhosin, Marc Mousli, Ziad Omran, Mazin A Zamzami, Abdulrahman L Almalki, Hani Choudhry, Christian BronnerAbstract:Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.
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cd47 activation induced UHRF1 over expression is associated with silencing of tumor suppressor gene p16ink4a in glioblastoma cells
Anticancer Research, 2015Co-Authors: Abdelaziz Boukhari, Christian Bronner, Valerie B Schinikerth, Mahmoud Alhosin, Krizia Sagini, Cecile Truchot, Emilie Sick, Philippe Andre, Yves Mely, Marc MousliAbstract:CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
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epigallocatechin 3 gallate up regulates tumor suppressor gene expression via a reactive oxygen species dependent down regulation of UHRF1
Biochemical and Biophysical Research Communications, 2012Co-Authors: Mayada Achour, Valerie B Schinikerth, Mahmoud Alhosin, Marc Mousli, Abdulkhaleg Ibrahim, Jean Peluso, Christian D Muller, Ali Hamiche, Sirano Dhepaganon, Christian BronnerAbstract:Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) contributes to silencing of tumor suppressor genes by recruiting DNA methyltransferase 1 (DNMT1) to their hemi-methylated promoters. Conversely, demethylation of these promoters has been ascribed to the natural anti-cancer drug, epigallocatechin-3-gallate (EGCG). The aim of the present study was to investigate whether the UHRF1/DNMT1 pair is an important target of EGCG action. Here, we show that EGCG down-regulates UHRF1 and DNMT1 expression in Jurkat cells, with subsequent up-regulation of p73 and p16(INK4A) genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16(INK4A) is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16(INK4A) and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16(INK4A) and p73, either in the presence or absence of EGCG. Our results show that down-regulation of UHRF1 is upstream to many cellular events, including G1 cell arrest, up-regulation of tumor suppressor genes and apoptosis.
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down regulation of UHRF1 associated with re expression of tumor suppressor genes is a common feature of natural compounds exhibiting anti cancer properties
Journal of Experimental & Clinical Cancer Research, 2011Co-Authors: Mahmoud Alhosin, Valerie B Schinikerth, Tanveer Sharif, Marc Mousli, Nelly Etienneselloum, Guy Fuhrmann, Christian BronnerAbstract:Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.
Valerie B Schinikerth - One of the best experts on this subject based on the ideXlab platform.
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cd47 activation induced UHRF1 over expression is associated with silencing of tumor suppressor gene p16ink4a in glioblastoma cells
Anticancer Research, 2015Co-Authors: Abdelaziz Boukhari, Christian Bronner, Valerie B Schinikerth, Mahmoud Alhosin, Krizia Sagini, Cecile Truchot, Emilie Sick, Philippe Andre, Yves Mely, Marc MousliAbstract:CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
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epigallocatechin 3 gallate up regulates tumor suppressor gene expression via a reactive oxygen species dependent down regulation of UHRF1
Biochemical and Biophysical Research Communications, 2012Co-Authors: Mayada Achour, Valerie B Schinikerth, Mahmoud Alhosin, Marc Mousli, Abdulkhaleg Ibrahim, Jean Peluso, Christian D Muller, Ali Hamiche, Sirano Dhepaganon, Christian BronnerAbstract:Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) contributes to silencing of tumor suppressor genes by recruiting DNA methyltransferase 1 (DNMT1) to their hemi-methylated promoters. Conversely, demethylation of these promoters has been ascribed to the natural anti-cancer drug, epigallocatechin-3-gallate (EGCG). The aim of the present study was to investigate whether the UHRF1/DNMT1 pair is an important target of EGCG action. Here, we show that EGCG down-regulates UHRF1 and DNMT1 expression in Jurkat cells, with subsequent up-regulation of p73 and p16(INK4A) genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16(INK4A) is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16(INK4A) and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16(INK4A) and p73, either in the presence or absence of EGCG. Our results show that down-regulation of UHRF1 is upstream to many cellular events, including G1 cell arrest, up-regulation of tumor suppressor genes and apoptosis.
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down regulation of UHRF1 associated with re expression of tumor suppressor genes is a common feature of natural compounds exhibiting anti cancer properties
Journal of Experimental & Clinical Cancer Research, 2011Co-Authors: Mahmoud Alhosin, Valerie B Schinikerth, Tanveer Sharif, Marc Mousli, Nelly Etienneselloum, Guy Fuhrmann, Christian BronnerAbstract:Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.
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UHRF1 recruits the histone acetyltransferase tip60 and controls its expression and activity
Biochemical and Biophysical Research Communications, 2009Co-Authors: Mayada Achour, Thierry Chataigneau, Valerie B Schinikerth, Mahmoud Alhosin, Marc Mousli, Guy Fuhrmann, Philippe Ronde, Christian BronnerAbstract:Tat-interactive protein, 60 kDa (Tip60) is a histone acetyltransferase with specificity toward lysine 5 of histone H2A (H2AK5) and plays multiple roles in chromatin remodeling processes. Co-immunoprecipitation experiments performed on Jurkat cells, showed that Tip60 is present in the same macro-molecular complex as UHRF1 (Ubiquitin-like containing PHD and RING domain 1), DNMT1 (DNA methyltransferase 1), and HDAC1 (histone deacetylase 1). Furthermore, immunocytochemistry experiments confirmed that Tip60 co-localizes with the UHRF1/DNMT1 complex. Although down-regulation of UHRF1 by RNA interference enhanced Tip60 expression, a significant decrease of the level of acetylated H2AK5 was observed. Consistently, we have observed that down-regulation of Tip60 and DNMT1 by RNA interference, dramatically reduced the levels of acetylated H2AK5. Altogether, these results suggest that Tip60 is a novel partner of the epigenetic integration platform interplayed by UHRF1, DNMT1 and HDAC1 involved in the epigenetic code replication.
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the uhrf family oncogenes that are drugable targets for cancer therapy in the near future
Pharmacology & Therapeutics, 2007Co-Authors: Christian Bronner, Mayada Achour, Yoshimi Arima, Thierry Chataigneau, Hideyuki Saya, Valerie B SchinikerthAbstract:In this paper, we review the current literature about the UHRF family that in particular includes the UHRF1 and UHRF2 genes. Its members play a fundamental role in cell proliferation through different structural domains. These domains include a ubiquitin-like domain (NIRF_N), a plant homeodomain (PHD) domain, a SRA domain and a RING domain. The SRA domain has only been observed in this family probably conferring unique properties to it. The unique enzymatic activity so far identified in this family involves the RING finger that contains a ubiquitin E3 ligase activity toward, for instance, histones. The physiological roles played by the UHRF family are most likely exerted during embryogenic development and when proliferation is required in adults. Interestingly, UHRF members are putative oncogenes regulated by tumor suppressor genes, but they exert also a feedback control on these latter. Finally, we propose some new roles for this family, including regulation and/or inheritance of the epigenetic code. Alteration of these regulatory mechanisms, such as those occurring in cancer cells, may be involved in carcinogenesis. The reasons why the UHRF family could be an interesting target for developing anticancer drugs is also developed.
