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

Abdol Hossein Rezaeian; Chien Feng Li; Ching Yuan Wu; Xian Zhang; Jorge Delacerda; M. James You; Fei Han; Zhen Cai; Yun Seong Jeong; Guoxiang Jin; Liem Phan; Ping Chieh Chou; Mong Hong Lee; Mien Chie Hung; Dos Sarbassov; Hui Kuan Lin

doi:10.1038/ncb3445

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

Abdol Hossein Rezaeian, Chien Feng Li, Ching Yuan Wu, Xian Zhang, Jorge Delacerda, M. James You, Fei Han, Zhen Cai, Yun Seong Jeong, Guoxiang Jin, Liem Phan, Ping Chieh Chou, Mong Hong Lee, Mien Chie Hung, Dos Sarbassov, Hui Kuan Lin

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79 Scopus citations

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 3H2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and 3H2AX-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.

Original language	English (US)
Pages (from-to)	38-51
Number of pages	14
Journal	Nature cell biology
Volume	19
Issue number	1
DOIs	https://doi.org/10.1038/ncb3445
State	Published - Jan 1 2017

ASJC Scopus subject areas

Cell Biology

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10.1038/ncb3445

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Rezaeian, A. H., Li, C. F., Wu, C. Y., Zhang, X., Delacerda, J., You, M. J., Han, F., Cai, Z., Jeong, Y. S., Jin, G., Phan, L., Chou, P. C., Lee, M. H., Hung, M. C., Sarbassov, D., & Lin, H. K. (2017). A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis. Nature cell biology, 19(1), 38-51. https://doi.org/10.1038/ncb3445

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

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 3H2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and 3H2AX-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.",

author = "Rezaeian, {Abdol Hossein} and Li, {Chien Feng} and Wu, {Ching Yuan} and Xian Zhang and Jorge Delacerda and You, {M. James} and Fei Han and Zhen Cai and Jeong, {Yun Seong} and Guoxiang Jin and Liem Phan and Chou, {Ping Chieh} and Lee, {Mong Hong} and Hung, {Mien Chie} and Dos Sarbassov and Lin, {Hui Kuan}",

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AU - Zhang, Xian

AU - Delacerda, Jorge

AU - You, M. James

AU - Han, Fei

AU - Cai, Zhen

AU - Jeong, Yun Seong

AU - Jin, Guoxiang

AU - Phan, Liem

AU - Chou, Ping Chieh

AU - Lee, Mong Hong

AU - Hung, Mien Chie

AU - Sarbassov, Dos

AU - Lin, Hui Kuan

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 3H2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and 3H2AX-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.

AB - 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 3H2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and 3H2AX-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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A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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