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

Abstract

SUMMARY 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.

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

“…1D). In a recent study, Ding and colleagues found that G9a requires ATF4 for transcriptional activation of serine biosynthesis enzymes, which increases the source of GSH biosynthesis and procancer metabolism (48). In view of these findings, we suggest the cooperation between G9a and ATF4 keeps the cancer cells in cellular redox balance.…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…It was reported recently that, upon serine starvation, p53 activates p21 to promote GSH production to combat ROS [25,26]. Additionally, p73, ATF4, G9A, HIF1 and PKCζ were also reported to regulate serine biosynthesis and metabolism [27][28][29][30][31]. However, compared to the profound understanding of glycolysis and glutaminolysis in cancer cells, we are only beginning to appreciate the critical impact of serine synthesis pathway (SSP) on cancer progression.…”

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

“…G9a inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. 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 (32).…”

“…The evidence that in mouse models of acute myeloid leukemia, loss of G9a significantly delays disease progression and reduces leukemia stem cell frequency (69) provides further evidence of a tumorigenic role of elevated levels of G9a. Interestingly, G9a has been recently shown to sustain cancer cell survival and proliferation by transcriptional activation, through deposition of H3K9me1, of the serine-glycine biosynthetic pathway (32). G9a inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins.…”