Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation

Abstract

Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1α/2α methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis.

Chromatin associated SETD3 negatively regulates VEGF expression

“…Liu and co-workers25 recently showed that HIF1 alpha and HIF2 alpha are methylated by SETD7 on lysines 32 and 29, respectively. This methylation inhibits the expression of HIF1/2 target genes.…”

Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

“…However, the classification may not be accurate, because some agents target more than one mechanism and it may be inappropriate to include them in a definite category. The targets and mechanisms of HIF inhibitors (Table 1) and some evaluated in clinical trials [Data were obtained from National Clinical Trial (https://clinicaltrials.gov)] are summarized 3031323334353637383940414243444546474849505152535455…”

“…2-methoxyestradiol (2ME2) is a product of estrogen metabolite and naturally produced by catechol-O-methyltransferase-mediated O-methylation of 2-hydroxyestradiol. 2ME2 was initially considered to disrupt microtubules, and later found to inhibit synthesis of HIF-1α and HIF-2α proteins, and suppress their nuclear translocation and transcriptional activity 3536. In ongoing phase II trials, 2ME2 is administered alone or in combination with other agents to treat various advanced or metastatic solid tumors (NCT00592579, NCT00481455, and NCT0044431).…”

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

“…SET7/9 is also enriched at the hypoxia response elements of a subset of HIF-1 regulated genes LDHA , HK2 , and PDK1 , and increases transcription of these glycolytic genes in hypoxic cells [44]. In contrast, Xiao and his colleagues recently showed that SET7/9 directly induces monomethylation of HIF-1α at K32 and of HIF-2α at K29, leading to suppression of HIF transcriptional activity without affecting their protein levels [45]. Knockdown of SET7/9 increases HIF-1α binding to the hypoxia response element to promote HIF-1 transcriptional activity and expression of the glycolytic genes in human clear cell renal carcinoma RCC4 cells, thereby increasing glucose uptake and ATP production.…”