A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1? activation, tumorigenesis and metastasis.

ABSTRACT: The understanding of how hypoxia stabilizes and activates HIF1? 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 HIF1? signalling. H2AX interacts with HIF1? to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1? 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 HIF1?-driven tumorigenesis. Importantly, TRAF6 and ?H2AX are overexpressed in human breast cancer, correlate with activation of HIF1? signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and ?H2AX-mediated HIF1? enrichment in the nucleus of cancer cells lead to overactivation of HIF1?-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.

SUBMITTER: Rezaeian AH 

PROVIDER: S-EPMC5441459 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature