The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2013 Dec 10

PMID 24315373

Citations 137

Authors

Jane Ding

Tai Li

Xiangwei Wang

Erhu Zhao

Jeong-Hyeon Choi

Liqun Yang

Yunhong Zha

Zheng Dong

Shuang Huang

John M Asara

Hongjuan Cui

Han-Fei Ding

Affiliations

Soon will be listed here.

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.

Citing Articles

EHMT2-mediated R-loop formation promotes the malignant progression of prostate cancer via activating Aurora B.

Zhang Y, Su M, Chen Y, Cui L, Xia W, Xu R Clin Transl Med. 2025; 15(1):e70164.

PMID: 39763034 PMC: 11705492. DOI: 10.1002/ctm2.70164.

Interplay between acetylation and ubiquitination controls PSAT1 protein stability in lung adenocarcinoma.

Liu Y, Xun W, Zhao T, Huang M, Sun L, Wen G Commun Biol. 2024; 7(1):1365.

PMID: 39433916 PMC: 11494179. DOI: 10.1038/s42003-024-07051-2.

Menin in Cancer.

Majer A, Hua X, Katona B Genes (Basel). 2024; 15(9).

PMID: 39336822 PMC: 11431421. DOI: 10.3390/genes15091231.

Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity.

Ma C, Lin Z, Yao J, Qin W, Wang X, Li Q Cancer Sci. 2024; 115(12):3902-3914.

PMID: 39327097 PMC: 11611778. DOI: 10.1111/cas.16336.

A metabolic crosstalk between liposarcoma and muscle sustains tumor growth.

Manteaux G, Amsel A, Riquier-Morcant B, Prieto Romero J, Gayte L, Fourneaux B Nat Commun. 2024; 15(1):7940.

PMID: 39266552 PMC: 11393074. DOI: 10.1038/s41467-024-51827-3.

References

Cho H, Kelly J, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M . Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia. 2011; 13(8):676-84. PMC: 3156658. DOI: 10.1593/neo.11512. View

Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M . G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002; 16(14):1779-91. PMC: 186403. DOI: 10.1101/gad.989402. View

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

Pollari S, Kakonen S, Edgren H, Wolf M, Kohonen P, Sara H . Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat. 2010; 125(2):421-30. DOI: 10.1007/s10549-010-0848-5. View

Shinkai Y, Tachibana M . H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev. 2011; 25(8):781-8. PMC: 3078703. DOI: 10.1101/gad.2027411. View

Lee T, Johnstone S, Young R . Chromatin immunoprecipitation and microarray-based analysis of protein location. Nat Protoc. 2007; 1(2):729-48. PMC: 3004291. DOI: 10.1038/nprot.2006.98. View

Possemato R, Marks K, Shaul Y, Pacold M, Kim D, Birsoy K . Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011; 476(7360):346-50. PMC: 3353325. DOI: 10.1038/nature10350. View

Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K . Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001; 152(4):657-68. PMC: 2195787. DOI: 10.1083/jcb.152.4.657. View

Kilberg M, Pan Y, Chen H, Leung-Pineda V . Nutritional control of gene expression: how mammalian cells respond to amino acid limitation. Annu Rev Nutr. 2005; 25:59-85. PMC: 3600373. DOI: 10.1146/annurev.nutr.24.012003.132145. View

10.

Ye J, Mancuso A, Tong X, Ward P, Fan J, Rabinowitz J . Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci U S A. 2012; 109(18):6904-9. PMC: 3345000. DOI: 10.1073/pnas.1204176109. View

11.

Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D . G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010; 285(13):9636-9641. PMC: 2843213. DOI: 10.1074/jbc.M109.062588. View

12.

He C, Klionsky D . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67-93. PMC: 2831538. DOI: 10.1146/annurev-genet-102808-114910. View

13.

Teperino R, Schoonjans K, Auwerx J . Histone methyl transferases and demethylases; can they link metabolism and transcription?. Cell Metab. 2010; 12(4):321-327. PMC: 3642811. DOI: 10.1016/j.cmet.2010.09.004. View

14.

Narkewicz M, Sauls S, Tjoa S, Teng C, Fennessey P . Evidence for intracellular partitioning of serine and glycine metabolism in Chinese hamster ovary cells. Biochem J. 1996; 313 ( Pt 3):991-6. PMC: 1217008. DOI: 10.1042/bj3130991. View

15.

Chen M, Hua K, Kao H, Chi C, Wei L, Johansson G . H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010; 70(20):7830-40. DOI: 10.1158/0008-5472.CAN-10-0833. View

16.

Grummt I, Ladurner A . A metabolic throttle regulates the epigenetic state of rDNA. Cell. 2008; 133(4):577-80. DOI: 10.1016/j.cell.2008.04.026. View

17.

Black J, Van Rechem C, Whetstine J . Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012; 48(4):491-507. PMC: 3861058. DOI: 10.1016/j.molcel.2012.11.006. View

18.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T . The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-6. DOI: 10.1038/nature03029. View

19.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

20.

Roberts A, Pimentel H, Trapnell C, Pachter L . Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics. 2011; 27(17):2325-9. DOI: 10.1093/bioinformatics/btr355. View