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NQO1 Inhibits Proteasome-Mediated Degradation of HIF-1α

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, Heon Joo Park

Nat Commun. 2016 Dec 14;7:13593.

PMID: 27966538

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415148	DT Diaphorase (NQO1) human			Price

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