The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation

Cell Metab. 2013 Dec 3;18(6):896-907. doi: 10.1016/j.cmet.2013.11.004.


Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for 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

  • Animals
  • Autophagy / drug effects
  • Azepines / pharmacology
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Epigenomics*
  • Glycine / biosynthesis*
  • HeLa Cells
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Methylation
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Quinazolines / pharmacology
  • Ribosomes / metabolism
  • Serine / biosynthesis*
  • Serine / pharmacology
  • Transcription, Genetic / drug effects


  • Azepines
  • BIX 01294
  • Histocompatibility Antigens
  • Histones
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • Quinazolines
  • Serine
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Glycine

Associated data

  • GEO/GSE51512