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 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.
authors.affiliation: 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.
authors.forename: Abdol-Hossein
authors.initials: AH
authors.lastname: Rezaeian
authors.affiliation: Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Delacerda
authors.affiliation: 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.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Molecular and Cellular Oncology, 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.
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Liem
authors.initials: L
authors.lastname: Phan
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Ping-Chieh
authors.initials: PC
authors.lastname: Chou
authors.affiliation: Department of Molecular and Cellular Oncology, 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.
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, 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.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Molecular and Cellular Oncology, 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.
authors.forename: Dos
authors.initials: D
authors.lastname: Sarbassov
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Cancer Biology, Wake Forest University School of Medicine Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D009362:Neoplasm Metastasis; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D016896:Treatment Outcome; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse