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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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the Epigenetic integrator uhrf1 on the road to become a universal biomarker for cancer
Oncotarget, 2017Co-Authors: Waseem Ashraf, Mahmoud Alhosin, Yves Mely, Abdulkhaleg Ibrahim, Liliyana Zaayter, Khalid Ouararhni, Christophe Papin, Tanveer Ahmad, Ali Hamiche, Christian BronnerAbstract:// Waseem Ashraf 1 , Abdulkhaleg Ibrahim 2 , Mahmoud Alhosin 3,4,5 , Liliyana Zaayter 1 , Khalid Ouararhni 2 , Christophe Papin 2 , Tanveer Ahmad 1 , Ali Hamiche 2 , Yves Mely 1 , Christian Bronner 2,* and Marc Mousli 1,* 1 Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France 2 Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg, Illkirch-Graffenstaden, France 3 Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia 4 Cancer Metabolism and Epigenetic Unit, King Abdulaziz University, Jeddah, Saudi Arabia 5 Cancer and Mutagenesis Unit, King Fahd Centre for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia * These authors are co-last authors Correspondence to: Marc Mousli, email: // Keywords : cancer, biomarkers, Epigenetics, UHRF1, DNA methylation Received : February 03, 2017 Accepted : April 02, 2017 Published : April 24, 2017 Abstract Cancer is one of the deadliest diseases in the world causing record number of mortalities in both developed and undeveloped countries. Despite a lot of advances and breakthroughs in the field of oncology still, it is very hard to diagnose and treat the cancers at early stages. Here in this review we analyze the potential of Ubiquitin-like containing PHD and Ring Finger domain 1 (UHRF1) as a universal biomarker for cancers. UHRF1 is an important Epigenetic regulator maintaining DNA methylation and histone Code in the cell. It is highly expressed in a variety of cancers and is a well-known oncogene that can disrupt the Epigenetic Code and override the senescence machinery. Many studies have validated UHRF1 as a powerful diagnostic and prognostic tool to differentially diagnose cancer, predict the therapeutic response and assess the risk of tumor progression and recurrence. Highly sensitive, non-invasive and cost effective approaches are therefore needed to assess the level of UHRF1 in patients, which can be deployed in diagnostic laboratories to detect cancer and monitor disease progression.
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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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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.
Zdenko Herceg - One of the best experts on this subject based on the ideXlab platform.
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deciphering the Epigenetic Code an overview of dna methylation analysis methods
Antioxidants & Redox Signaling, 2013Co-Authors: Muhammad Umer, Zdenko HercegAbstract:Abstract Significance: Methylation of cytosine in DNA is linked with gene regulation, and this has profound implications in development, normal biology, and disease conditions in many eukaryotic organisms. A wide range of methods and approaches exist for its identification, quantification, and mapping within the genome. While the earliest approaches were nonspecific and were at best useful for quantification of total methylated cytosines in the chunk of DNA, this field has seen considerable progress and development over the past decades. Recent Advances: Methods for DNA methylation analysis differ in their coverage and sensitivity, and the method of choice depends on the intended application and desired level of information. Potential results include global methyl cytosine content, degree of methylation at specific loci, or genome-wide methylation maps. Introduction of more advanced approaches to DNA methylation analysis, such as microarray platforms and massively parallel sequencing, has brought us close...
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Epigenetic information in chromatin the Code of entry for dna repair
Cell Cycle, 2006Co-Authors: Joanna I Loizou, Rabih Murr, Martin G Finkbeiner, Carla Sawan, Zhaoqi Wang, Zdenko HercegAbstract:Epigenetic changes are important etiological factors of human cancer. Epigenetic information in chromatin (known as 'histone Code') is a fascinating feature used by cells to extend and modulate the genetic (DNA) Code. The histone Code is thus proposed to be 'read' by cells to regulate accessibility to, and functions of, chromatin DNA. While the role of the Epigenetic Code involving chromatin modifying/remodeling complexes in transcriptional regulation is well established, it is only recently that these mechanisms have been implicated in DNA damage detection and DNA repair. However, how the components of the DNA damage sensing and repair machinery gain access to broken DNA in compacted chromatin remains a mystery. Recent studies in this field provide important insights into DNA damage-specific and DNA repair-specific modifications to histones and encourage us that the Epigenetic Code in chromatin during DNA repair will be understood in terms of precisely defined players and mechanisms.
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Epigenetic information in chromatin the Code of entry for dna repair
Cell Cycle, 2006Co-Authors: Joanna I Loizou, Rabih Murr, Martin G Finkbeiner, Carla Sawan, Zhaoqi Wang, Zdenko HercegAbstract:Epigenetic changes are important etiological factors of human cancer. Epigenetic information in chromatin (known as 'histone Code') is a fascinating feature used by cells to extend and modulate the genetic (DNA) Code. The histone Code is thus proposed to be 'read' by cells to regulate accessibility to, and functions of, chromatin DNA. While the role of the Epigenetic Code involving chromatin modifying/remodeling complexes in transcriptional regulation is well established, it is only recently that these mechanisms have been implicated in DNA damage detection and DNA repair. However, how the components of the DNA damage sensing and repair machinery gain access to broken DNA in compacted chromatin remains a mystery. Recent studies provide important insights into DNA damage- and repair-specific modifications to histones and shed light on how the Epigenetic Code controls DNA repair.
Mahmoud Alhosin - One of the best experts on this subject based on the ideXlab platform.
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Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
SAGE Publishing, 2019Co-Authors: Shahad A Qadi, Mazin A Zamzami, Hani Choudhry, Mohammed A Hassan, Ryan A Sheikh, Othman As Baothman, Abdulrahman Labeed Al-malki, Ashwag Albukhari, Mahmoud AlhosinAbstract:The Epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various Epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the Epigenetic Code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key Epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 ( UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B , and KMT2A,B,C,D,E , were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4 , and DDIT3 , known to be Epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD , and BIK . Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of UHRF1, DNMT1, G9a , and HDAC1 genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an Epigenetic drug represents a promising strategy for Epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications
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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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the Epigenetic integrator uhrf1 on the road to become a universal biomarker for cancer
Oncotarget, 2017Co-Authors: Waseem Ashraf, Mahmoud Alhosin, Yves Mely, Abdulkhaleg Ibrahim, Liliyana Zaayter, Khalid Ouararhni, Christophe Papin, Tanveer Ahmad, Ali Hamiche, Christian BronnerAbstract:// Waseem Ashraf 1 , Abdulkhaleg Ibrahim 2 , Mahmoud Alhosin 3,4,5 , Liliyana Zaayter 1 , Khalid Ouararhni 2 , Christophe Papin 2 , Tanveer Ahmad 1 , Ali Hamiche 2 , Yves Mely 1 , Christian Bronner 2,* and Marc Mousli 1,* 1 Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France 2 Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg, Illkirch-Graffenstaden, France 3 Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia 4 Cancer Metabolism and Epigenetic Unit, King Abdulaziz University, Jeddah, Saudi Arabia 5 Cancer and Mutagenesis Unit, King Fahd Centre for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia * These authors are co-last authors Correspondence to: Marc Mousli, email: // Keywords : cancer, biomarkers, Epigenetics, UHRF1, DNA methylation Received : February 03, 2017 Accepted : April 02, 2017 Published : April 24, 2017 Abstract Cancer is one of the deadliest diseases in the world causing record number of mortalities in both developed and undeveloped countries. Despite a lot of advances and breakthroughs in the field of oncology still, it is very hard to diagnose and treat the cancers at early stages. Here in this review we analyze the potential of Ubiquitin-like containing PHD and Ring Finger domain 1 (UHRF1) as a universal biomarker for cancers. UHRF1 is an important Epigenetic regulator maintaining DNA methylation and histone Code in the cell. It is highly expressed in a variety of cancers and is a well-known oncogene that can disrupt the Epigenetic Code and override the senescence machinery. Many studies have validated UHRF1 as a powerful diagnostic and prognostic tool to differentially diagnose cancer, predict the therapeutic response and assess the risk of tumor progression and recurrence. Highly sensitive, non-invasive and cost effective approaches are therefore needed to assess the level of UHRF1 in patients, which can be deployed in diagnostic laboratories to detect cancer and monitor disease progression.
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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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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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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 Epigenetic Code replication machinery ecrem a promising drugable target of the Epigenetic cell memory
Current Medicinal Chemistry, 2007Co-Authors: Christian Bronner, Thierry Chataigneau, Valerie B Schinikerth, Y LandryAbstract:Discrete chemical modifications of the chromatin (DNA and primarily histones) can regulate gene expression or repression and can be transmitted to the descent (cells or organisms) thanks to an Epigenetic memory. These modifications involve histone post-translational modifications, DNA methylation at CpG islands and small nuclear RNAs processes. They play fundamental roles in cell proliferation and differentiation. These two processes are crucial in particular during embryonic development, X chromosome inactivation in females, genomic imprinting, gene bookmarking, cell reprogramming, position effect and silencing of retroviral elements. While, only one major DNA modification is known, more than 150 post-translation modifications of histones have been reported, including methylations, acetylations, ubiquitinations, SUMOylations and phosphorylations. How these modifications are inherited from mother cells to daughter cells or from an organism to its descent remains a major scientific challenge. We propose here a macro-molecular complex, called ECREM for "Epigenetic Code REplication Machinery", as being involved in the inheritance of the Epigenetic Code. The composition of ECREM may vary in a spatio-temporal manner according to the chromatin state, the cell phenotype and the development stage. We describe the members of ECREM, responsible for the Epigenetic Code inheritance, i.e., enzymes involved in DNA methylation and histone post-translational modifications. Some of them, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACS including sirtuins), have been found to be deregulated in several types of pathologies and are already targeted by inhibitors. ECREM, thus, appears to be an interesting complex to be investigated in order to find new drugs for cancer, metabolic, neuro-degenerative and inflammatory diseases therapy.
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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.
Bryan M Turner - One of the best experts on this subject based on the ideXlab platform.
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Defining an Epigenetic Code
Nature Cell Biology, 2007Co-Authors: Bryan M TurnerAbstract:The nucleosome surface is decorated with an array of enzyme-catalysed modifications on histone tails. These modifications have well-defined roles in a variety of ongoing chromatin functions, often by acting as receptors for non-histone proteins, but their longer-term effects are less clear. Here, an attempt is made to define how histone modifications operate as part of a predictive and heritable Epigenetic Code that specifies patterns of gene expression through differentiation and development.
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Histone modifications : signalling receptors and potential elements of a heritable Epigenetic Code
Current Opinion in Genetics & Development, 2006Co-Authors: Karl P. Nightingale, Laura P. O'neill, Bryan M TurnerAbstract:The genetic Code epitomises simplicity, near universality and absolute predictive power. By contrast, Epigenetic information, in the form of histone modifications, is characterised by complexity, diversity and an overall tendency to respond to changes in genomic function rather than to predict them. Perhaps the transient changes in histone modifications involved in intranuclear signalling and ongoing chromatin functions mask stable, predictive modifications that lie beneath. The current rapid progress in unravelling the diversity and complexity of Epigenetic information might eventually reveal an underlying histone or Epigenetic Code. But whether it does or not, it will certainly provide unprecedented opportunities, both for understanding how the genome responds to environmental and metabolic change and for manipulating its activities for experimental and therapeutic benefit.
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Histone acetylation and an Epigenetic Code
BioEssays, 2000Co-Authors: Bryan M TurnerAbstract:Summary The enzyme-catalyzed acetylation of the N-terminal tail domains of core histones provides a rich potential source of Epigenetic information. This may be used both to mediate transient changes in transcription, through modification of promoter-proximal nucleosomes, and for the longer-term maintenance and modulation of patterns of gene expression. The latter may be achieved by setting specific patterns of histone acetylation, perhaps involving acetylation of particular lysine residues, across relatively large chromatin domains. The histone acetylating and deacetylating enzymes (HATs and HDACs, respectively) can be targeted to specific regions of the genome and show varying degrees of substrate specificity, properties that are consistent with a role in maintaining a dynamic, acetylation-based Epigenetic Code. The Code may be read (ie. exert a functional effect) either through non-histone proteins that bind in an acetylation-dependent manner, or through direct effects on chromatin structure. Recent evidence raises the interesting possibility that an acetylationbased Code may operate through both mitosis and meiosis, providing a possible mechanism for germ-line transmission of Epigenetic changes. BioEssays 22:836‐845, 2000. fl 2000 John Wiley & Sons, Inc.