Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex

Neoplasia. 2013 May;15(5):511-22. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Acetylation
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / metabolism
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Repressor Proteins / metabolism*

Substances

  • 5' Untranslated Regions
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Chromatin
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • MECP2 protein, human
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • SIN3A transcription factor
  • trichostatin A
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases