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

Nature Cell Biology volume 19, pages 3851 (2017) | Download Citation

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.

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Acknowledgements

We thank F. Alt (Harvard University, USA) for providing H2AX null mice. We also thank S. Piccolo (University of Podova, Italy), X. Lin (The University of Texas MD Anderson Cancer Center, USA), J. Chen (The University of Texas MD Anderson Cancer Center, USA), M. D. Bohmann (University of Rochester, USA), M. Eilers (University of Wurzburg, Germany), J. L. Wrana (Mount Sinai Hospital, Canada), X. Yang (University of Pennsylvania, USA), J. Cheng (Shanghai Jiao Tong University, China), E. Yeh (University of Missouri, USA), Z. Lou (Mayo Clinic, USA) and B. Gan (The University of Texas MD Anderson Cancer Center, USA) for reagents and equipment. This work was supported by NIH R01 grants (R01CA182424-01A1, R01CA193813-01), the MD Anderson Cancer Center SPORE development grant, the R. Clark Fellowship award, MD Anderson Cancer Center Prostate Moonshot Program funds, and Start-up funds from Wake Forest University School of Medicine to H.-K.L. and MOST104-2314-B-384-009-MY3 and MOHW104-TDU-M-212-133004 grants from Taiwan to C.-F.L.

Author information

Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Abdol-Hossein Rezaeian
    • , Ching-Yuan Wu
    • , Xian Zhang
    • , 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
  2. Department of Molecular Medicine, Pasteur Institute, Tehran 13169, Iran

    • Abdol-Hossein Rezaeian
  3. Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan

    • Chien-Feng Li
  4. National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan

    • Chien-Feng Li
  5. Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA

    • Xian Zhang
    • , Fei Han
    • , Zhen Cai
    • , Guoxiang Jin
    • , Ping-Chieh Chou
    •  & Hui-Kuan Lin
  6. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jorge Delacerda
  7. The University of Texas Graduate School of Biomedical Sciences at Houston, Texas 77030, USA

    • M. James You
    • , Yun Seong Jeong
    • , Mong-Hong Lee
    • , Mien-Chie Hung
    •  & Dos Sarbassov
  8. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • M. James You
  9. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

    • Mien-Chie Hung
  10. Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan

    • Hui-Kuan Lin
  11. Department of Biotechnology, Asia University, Taichung 413, Taiwan

    • Hui-Kuan Lin

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Contributions

A.-H.R. and H.-K.L. co-conceived the project, designed the experiments, analysed the data and wrote the manuscript. A.-H.R. performed the experiments with assistance from C.-Y.W., X.Z., F.H., Z.C., Y.S.J., G.J., L.P. and P.-C.C. C.-F.L. performed the immunohistochemistry experiments with human subjects and analysed the data. J.D. and M.J.Y. helped A.-H.R. with the CT/PET imaging and mouse tumour analysis, respectively. M.-H.L., M.-C.H. and D.S. provided the input and suggestions.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Abdol-Hossein Rezaeian or Hui-Kuan Lin.

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DOI

https://doi.org/10.1038/ncb3445

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