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

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

Author information

1
Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
2
State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400716, China.
3
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing 400037, China.
4
Department of Biostatistics and Epidemiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
5
Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 423000, China.
6
Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
7
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
8
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
#
Contributed equally

Abstract

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.

PMID:
24315373
PMCID:
PMC3878056
DOI:
10.1016/j.cmet.2013.11.004
[Indexed for MEDLINE]
Free PMC Article

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