Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer

Mol Cell. 2013 Jan 10;49(1):80-93. doi: 10.1016/j.molcel.2012.10.008. Epub 2012 Nov 15.

Abstract

Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.

Publication types

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

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Chick Embryo
  • Chorioallantoic Membrane / pathology
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tissue Array Analysis
  • Transcriptional Activation

Substances

  • 3' Untranslated Regions
  • Histones
  • MicroRNAs
  • Repressor Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • Polycomb Repressive Complex 2

Associated data

  • GEO/GSE41653