MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

Cancer Cell. 2018 Oct 8;34(4):579-595.e8. doi: 10.1016/j.ccell.2018.09.001.


MYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.

Keywords: BioID; G9a; MYC; breast cancer; epigenetic therapy; histone methylation; transcriptional repression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Epigenesis, Genetic / genetics
  • Gene Expression / genetics*
  • Histocompatibility Antigens / genetics
  • Histone Methyltransferases / genetics*
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Mice
  • Promoter Regions, Genetic / genetics
  • Transcription Factors / genetics*


  • Histocompatibility Antigens
  • Transcription Factors
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase