國家衛生研究院 NHRI:Item 3990099045/10184
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/10184


    Title: A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1alpha activation, tumorigenesis and metastasis
    Other Titles: A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis
    Authors: Rezaeian, AH;Li, CF;Wu, CY;Zhang, X;Delacerda, J;You, MJ;Han, F;Cai, Z;Jeong, YS;Jin, G;Phan, L;Chou, PC;Lee, MH;Hung, MC;Sarbassov, D;Lin, HK
    Contributors: National Institute of Cancer Research
    Abstract: The understanding of how hypoxia stabilizes and activates HIF1alpha 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 HIF1alpha signalling. H2AX interacts with HIF1alpha to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1alpha 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 HIF1alpha-driven tumorigenesis. Importantly, TRAF6 and gammaH2AX are overexpressed in human breast cancer, correlate with activation of HIF1alpha signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and gammaH2AX-mediated HIF1alpha enrichment in the nucleus of cancer cells lead to overactivation of HIF1alpha-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.
    Date: 2017-01
    Relation: Nature Cell Biology. 2017 Jan;19(1):38-51.
    Link to: http://dx.doi.org/10.1038/ncb3445
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1465-7392&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000391349000007
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85002323659
    Appears in Collections:[Others] Periodical Articles

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