Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the α subunit of HIF-1 (HIF-1α) and catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1α transactivation domain function but not increased HIF-1α protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…Growing evidence has revealed that the transcriptional activity of HIFs is regulated by epigenetic factors at multiple levels [ 71 , 72 ]. The stability of HIF-α subunits are the basis for biological function of HIF complexes and regulates hypoxia-related phenotypes of tumor cells in combination with other important epigenetic regulators [ 73 ].…”

“…Whether this indicates that G9a/GLP has direct effects on HIF-α activities via epigenetic regulation are still unknown. What we know is that G9a/GLP bind directly to HIF-1α protein in hypoxic tumors, both in vitro and in vivo, and catalyze monomethylation and dimethylation of HIF-1α at lysine 674, thereby inhibiting the transcriptional activity of HIF-1α and the expression of its downstream target genes [ 72 ]. For histone demethylases, the Jumonji domain (JMJD) containing protein and lysine-specific demethylase 1 (LSD1) involved in regulation of HIF stability [ 100 ].…”

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

“…EHMT2/G9a and EHMT1/GLP are key SET domain containing lysine methyltransferases that catalyze dimethylation of histone H3 lysine 9 (H3K9me2), resulting in transcriptional repression of target genes (22). Deregulated expression and function of G9a, and to a lesser extent GLP, have been reported in cancers of different origins (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). In addition to its canonical role in gene repression, G9a can also activate genes through association with coactivator complexes in a context-dependent manner (23).…”

Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis‐PROX1‐HIF‐1α in liver fibrosis

“…The ubiquitin‐proteasome system practically kept steady‐state levels low. Until recently, studies of post‐translational modifications of HIF‐1α were expanded to hydroxylation, phosphorylation, methylation and acetylation . In hepatocellular carcinoma, the homeobox protein PROX1 is overexpressed in hepatocytes and is required for cell migration.…”