Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex
Copyright policy )Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex
BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.
- University of Turin Italy
- UNSW Sydney Australia
- University of Milan Italy
- University of Milan Italy
- University of Milano-Bicocca Italy
Lymphoma, Methyl-CpG-Binding Protein 2, 32 Biomedical and Clinical Sciences, Hydroxamic Acids, anzsrc-for: 1103 Clinical Sciences, Epigenesis, Genetic, Histones, 2.1 Biological and endogenous factors, Anaplastic, 3202 Clinical Sciences, RC254-282, Cancer, Tumor, Bcl-2-Like Protein 11, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Acetylation, Hematology, Protein-Tyrosine Kinases, Chromatin, Large-Cell, Gene Expression Regulation, Neoplastic, Sin3 Histone Deacetylase and Corepressor Complex, Lymphoma, Large-Cell, Anaplastic, anzsrc-for: 3202 Clinical Sciences, Lymphatic Research, Cell Survival, 610, Cell Line, Rare Diseases, anzsrc-for: 32 Biomedical and Clinical Sciences, Genetic, Proto-Oncogene Proteins, Cell Line, Tumor, Genetics, Humans, BIM, gene silencing ; 5' untranslated regions; acetylation ; apoptosis regulatory proteins ; case-control studies ; cell line, tumor ; cell survival ; chromatin ; CpG Islands ; DNA methylation ; epigenesis, genetic ; gene expression regulation, neoplastic ; histone deacetylase inhibitors; histones ; humans ; hydroxamic acids ; lymphoma, large-cell, anaplastic ; membrane proteins ; Methyl-CpG-Binding Protein 2 ; protein processing, post-translational; protein-tyrosine kinases ; proto-oncogene proteins ; repressor proteins, Gene Silencing, Protein Processing, anzsrc-for: 3211 Oncology and Carcinogenesis, Neoplastic, Post-Translational, Membrane Proteins, DNA Methylation, 3211 Oncology and Carcinogenesis, Repressor Proteins, Histone Deacetylase Inhibitors, Gene Expression Regulation, Case-Control Studies, CpG Islands, 5' Untranslated Regions, Apoptosis Regulatory Proteins, Epigenesis
Lymphoma, Methyl-CpG-Binding Protein 2, 32 Biomedical and Clinical Sciences, Hydroxamic Acids, anzsrc-for: 1103 Clinical Sciences, Epigenesis, Genetic, Histones, 2.1 Biological and endogenous factors, Anaplastic, 3202 Clinical Sciences, RC254-282, Cancer, Tumor, Bcl-2-Like Protein 11, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Acetylation, Hematology, Protein-Tyrosine Kinases, Chromatin, Large-Cell, Gene Expression Regulation, Neoplastic, Sin3 Histone Deacetylase and Corepressor Complex, Lymphoma, Large-Cell, Anaplastic, anzsrc-for: 3202 Clinical Sciences, Lymphatic Research, Cell Survival, 610, Cell Line, Rare Diseases, anzsrc-for: 32 Biomedical and Clinical Sciences, Genetic, Proto-Oncogene Proteins, Cell Line, Tumor, Genetics, Humans, BIM, gene silencing ; 5' untranslated regions; acetylation ; apoptosis regulatory proteins ; case-control studies ; cell line, tumor ; cell survival ; chromatin ; CpG Islands ; DNA methylation ; epigenesis, genetic ; gene expression regulation, neoplastic ; histone deacetylase inhibitors; histones ; humans ; hydroxamic acids ; lymphoma, large-cell, anaplastic ; membrane proteins ; Methyl-CpG-Binding Protein 2 ; protein processing, post-translational; protein-tyrosine kinases ; proto-oncogene proteins ; repressor proteins, Gene Silencing, Protein Processing, anzsrc-for: 3211 Oncology and Carcinogenesis, Neoplastic, Post-Translational, Membrane Proteins, DNA Methylation, 3211 Oncology and Carcinogenesis, Repressor Proteins, Histone Deacetylase Inhibitors, Gene Expression Regulation, Case-Control Studies, CpG Islands, 5' Untranslated Regions, Apoptosis Regulatory Proteins, Epigenesis
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