Eun-Taex Oh^1,2,*, Jung-whan Kim^3,*, Joon Mee Kim⁴, Soo Jung Kim¹, Jae-Seon Lee^1,2, Soon-Sun Hong^1,2, Justin Goodwin³, Robin J. Ruthenborg³, Myung Gu Jung⁵, Hae-June Lee⁵, Chul-Ho Lee⁶, Eun Sung Park², Chulhee Kim⁷ & Heon Joo Park<sup>2,8

1</sup> Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea. ² Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea. ³ Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA. ⁴ Department of Pathology, College of Medicine, Inha University, Incheon 400-712, Republic of Korea. ⁵ Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea. ⁶ Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea. ⁷ Department of Polymer Science and Engineering, Inha University, Incheon 22212, Republic of Korea. ⁸ Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea. ^* These authors contributed equally to this work.

Correspondence to Heon Joo Park.

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.