Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase.
Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase.
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DOI：
10.1016/j.bbamcr.2015.01.011
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Qian DZ
中科院分区：
文献类型：
--
作者：
Liu Q;Geng H;Xue C;Beer TM;Qian DZ
HIF-1α通过氧依赖性机制降解，但在缺氧中稳定形成转录复合物HIF-1，其反式激活促进癌症标志的基因。然而，HIF-1α在缺氧中如何特异性调节还知之甚少。在这里，我们报告组蛋白甲基转移酶SET 9促进HIF-1α蛋白在缺氧中的稳定性，并增强HIF-1介导的糖酵解基因转录，从而在介导癌细胞对缺氧应激的适应和存活中发挥重要作用。具体而言，SET 9与HIF-1α相互作用并促进HIF-1α蛋白在缺氧中的稳定性。通过siRNA沉默SET 9可降低缺氧条件下HIF-1α蛋白的稳定性，并减弱介导缺氧糖酵解的HIF-1靶基因的缺氧诱导。从机制上讲，我们发现SET 9在HIF-1响应糖酵解基因启动子内的缺氧响应元件（HRE）处富集。沉默SET 9降低缺氧时这些HRE的HIF-1α水平，从而减弱HIF-1介导的基因转录。此外，通过siRNA沉默SET 9减少缺氧诱导的糖酵解并抑制缺氧癌细胞的细胞活力。我们的研究结果表明，缺氧时，SET 9富集在HIF-1响应性糖酵解基因的HRE位点，并稳定HIF-1α在这些位点，从而建立了缺氧癌细胞代谢适应的表观遗传机制。
HIF-1α is degraded by oxygen-dependent mechanisms but stabilized in hypoxia to form transcriptional complex HIF-1, which transactivates genes promoting cancer hallmarks. However, how HIF-1α is specifically regulated in hypoxia is poorly understood. Here, we report that the histone methyltransferase SET9 promotes HIF-1α protein stability in hypoxia and enhances HIF-1 mediated glycolytic gene transcription, thereby playing an important role in mediating cancer cell adaptation and survival to hypoxic stress. Specifically, SET9 interacts with HIF-1α and promotes HIF-1α protein stability in hypoxia. Silencing SET9 by siRNA reduces HIF-1α protein stability in hypoxia, and attenuates the hypoxic induction of HIF-1 target genes mediating hypoxic glycolysis. Mechanistically, we find that SET9 is enriched at the hypoxia response elements (HRE) within promoters of the HIF-1-responsive glycolytic genes. Silencing SET9 reduces HIF-1α levels at these HREs in hypoxia, thereby attenuating HIF-1-mediated gene transcription. Further, silencing SET9 by siRNA reduces hypoxia-induced glycolysis and inhibits cell viability of hypoxic cancer cells. Our findings suggest that SET9 enriches at HRE sites of HIF-1 responsive glycolytic genes and stabilizes HIF-1α at these sites in hypoxia, thus establishes an epigenetic mechanism of the metabolic adaptation in hypoxic cancer cells.
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