G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

Abstract

G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN. This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a-suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers.

Dual Targeting of Histone Methyltransferase G9a and DNA‐Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma

“…In solid tumors such as HCC, glycolysis is exacerbated by the protumorigenic hypoxic environment. (34) As recently found in breast cancer cells, (35) we observed that G9a protein levels were increased in HCC cells under hypoxia ( Fig. 5A and Supporting Fig.…”

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

“…polyubiquitination and proteasomal degradation of G9a (45). In our experimental conditions, however, PHD1-3 knockdown failed to increase G9a and GLP protein levels under normoxia, while it clearly stabilizes HIF-1 or HIF-2 (Fig.1D).…”

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

“…Pharmacological or genetic inhibition of G9a prevents tumorigenesis in mice [40, 41]. G9a is induced by hypoxia at both transcriptional and posttranslational levels in embryonic stem cells and cancer cells and may mediate hypoxia-induced gene repression through increasing dimethyl K9 of histone H3 in cancer cells [41–43]. However, the direct effect of G9a on HIF transcriptional activity remains unknown.…”