Abstract 458: Regulation of HIF1a by Set9 lysine methyltransferase

HIF-1 is consisted of an oxygen-sensitive HIF-1α and a constitutive HIF-1β subunit. The activity of HIF-1 is implicated in human cancer development. In normoxia, the HIF-1α subunit is constantly synthesized, but rapidly degraded by the oxygen-dependent mechanism. In hypoxia due to tumor growth and anti-angiogenic therapy, HIF-1α is stabilized and dimerizes with HIF-1β to form HIF-1, which transactivates genes promoting cancer hallmarks, including angiogenesis, metabolic reprogramming, migration and invasion. Notably, HIF-1 increases multiple genes on the glycolytic pathway, which mediates the metabolic adaptation of hypoxic stress. Therefore, HIF-1α is an intriguing anticancer target. However, how HIF-1α is regulated in hypoxia is poorly understood. Here, we report that the histone methyltransferaseSet9 promotes HIF-1α protein stability in hypoxia and plays an important role in cancer cell glycolytic adaptation. Specifically, Set9 interacts with HIF-1α to maintain its stability in hypoxia. Silencing of Set9 by siRNA in hypoxia significantly reduces HIF-1α protein level, reduces HIF-1 transcriptional activity, and attenuates expressions of HIF-1-responsive glycolytic genes as well as hypoxia-induced glycolysis. Further, we have found that Set9 binds to the chromatins of hypoxia response elements within HIF-1-responsive glycolytic genes. The results suggest that Set9 epigenetically contributes to the glycolytic phenotype of cancer through HIF-1. Citation Format: Qiong Liu, Hao Geng, Changhui Xue, Tomasz M. Beer, David Z. Qian. Regulation of HIF1aby Set9 lysine methyltransferase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 458. doi:10.1158/1538-7445.AM2014-458