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Nat Cell Biol. 2017 Jan;19(1):38-51. doi: 10.1038/ncb3445. Epub 2016 Dec 5.

A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.

Rezaeian AH1,2, Li CF3,4, Wu CY1, Zhang X1,5, Delacerda J6, You MJ7,8, Han F1,5, Cai Z1,5, Jeong YS1,7, Jin G1,5, Phan L1, Chou PC1,5, Lee MH1,7, Hung MC1,7,9, Sarbassov D1,7, Lin HK1,5,10,11.

Author information

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Molecular Medicine, Pasteur Institute, Tehran 13169, Iran.
Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
The University of Texas Graduate School of Biomedical Sciences at Houston, Texas 77030, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.
Department of Biotechnology, Asia University, Taichung 413, Taiwan.


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.

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