NQO1 inhibits proteasome-mediated degradation of HIF-1α

Eun-Taex Oh, Jung-whan Kim, Joon Mee Kim, Soo Jung Kim, Jae-Seon Lee, Soon-Sun Hong, Justin Goodwin, Robin J. Ruthenborg, Myung Gu Jung, Hae-June Lee, Chul-Ho Lee, Eun Sung Park, Chulhee Kim and Heon Joo Park ()
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Eun-Taex Oh: College of Medicine, Inha University
Jung-whan Kim: The University of Texas at Dallas
Joon Mee Kim: College of Medicine, Inha University
Soo Jung Kim: College of Medicine, Inha University
Jae-Seon Lee: College of Medicine, Inha University
Soon-Sun Hong: College of Medicine, Inha University
Justin Goodwin: The University of Texas at Dallas
Robin J. Ruthenborg: The University of Texas at Dallas
Myung Gu Jung: Korea Institute of Radiological and Medical Sciences
Hae-June Lee: Korea Institute of Radiological and Medical Sciences
Chul-Ho Lee: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu
Eun Sung Park: Hypoxia-related Disease Research Center, College of Medicine, Inha University
Chulhee Kim: Inha University
Heon Joo Park: Hypoxia-related Disease Research Center, College of Medicine, Inha University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.

Date: 2016
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DOI: 10.1038/ncomms13593

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