Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex
Articolo
Data di Pubblicazione:
2013
Citazione:
Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex / R. Piazza, V. Magistroni, A. Mogavero, F. Andreoni, C. Ambrogio, R. Chiarle, L. Mologni, P.S. Bachmann, R.B. Lock, P. Collini, G. Pelosi, C. Gambacorti Passerini. - In: NEOPLASIA. - ISSN 1522-8002. - 15:5(2013 May), pp. 511-522. [10.1593/neo.121784]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
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
Elenco autori:
R. Piazza, V. Magistroni, A. Mogavero, F. Andreoni, C. Ambrogio, R. Chiarle, L. Mologni, P.S. Bachmann, R.B. Lock, P. Collini, G. Pelosi, C. Gambacorti Passerini
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