title: Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON.
abstract: Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Yuh-Shyan
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Tzong-Shin
authors.initials: TS
authors.lastname: Tzai
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Hong-Ling
authors.initials: HL
authors.lastname: Cheng
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. chownh@mail.ncku.edu.tw.
authors.forename: Nan-Haw
authors.initials: NH
authors.lastname: Chow
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D006801:Humans; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014157:Transcription Factors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases