NQO1 inhibits proteasome-mediated degradation of HIF-1α.

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.
Mesh Terms:
Breast Neoplasms, Cell Line, Tumor, Colorectal Neoplasms, Gene Knockdown Techniques, Homeostasis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, NAD(P)H Dehydrogenase (Quinone), Oxygen, Proteasome Endopeptidase Complex, Protein Stability
Nat Commun
Date: Dec. 14, 2015
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