Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON

Hong Yi Chang, Hsiao Sheng Liu, Ming Derg Lai, Yuh Shyan Tsai, Tzong Shin Tzai, Hong Ling Cheng, Nan Haw Chow

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4549-4562
Number of pages14
JournalCancer Research
Volume74
Issue number16
DOIs
Publication statusPublished - 2014 Aug 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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