| Literature DB >> 27918549 |
Abdol-Hossein Rezaeian1,2, Chien-Feng Li3,4, Ching-Yuan Wu1, Xian Zhang1,5, Jorge Delacerda6, M James You7,8, Fei Han1,5, Zhen Cai1,5, Yun Seong Jeong1,7, Guoxiang Jin1,5, Liem Phan1, Ping-Chieh Chou1,5, Mong-Hong Lee1,7, Mien-Chie Hung1,7,9, Dos Sarbassov1,7, Hui-Kuan Lin1,5,10,11.
Abstract
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.Entities:
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Year: 2016 PMID： 27918549 PMCID： PMC5441459 DOI： 10.1038/ncb3445
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824