Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas

Cancer Cell. 2012 Oct 16;22(4):506-523. doi: 10.1016/j.ccr.2012.09.003.

Abstract

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Silencing
  • Histone Deacetylases / physiology*
  • Histones / metabolism*
  • Humans
  • Lymphoma, B-Cell / etiology*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / therapy
  • Methylation
  • Mice
  • MicroRNAs / analysis
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / physiology*
  • Polycomb Repressive Complex 2 / physiology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*

Substances

  • Histones
  • MIRN26A microRNA, human
  • MIRN29 microRNA, human
  • MIRN494 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE40019