NQO1 inhibits proteasome-mediated degradation of HIF-1α

被引：145

作者：

Oh, Eun-Taex ^{[1
,2
]}

Kim, Jung-whan ^{[3
]}

Kim, Joon Mee ^{[4
]}

Kim, Soo Jung ^{[1
]}

Lee, Jae-Seon ^{[1
,2
]}

Hong, Soon-Sun ^{[1
,2
]}

Goodwin, Justin ^{[3
]}

Ruthenborg, Robin J. ^{[3
]}

Jung, Myung Gu ^{[5
]}

Lee, Hae-June ^{[5
]}

Lee, Chul-Ho ^{[6
]}

Park, Eun Sung ^{[2
]}

Kim, Chulhee ^{[7
]}

Park, Heon Joo ^{[2
,8
]}

机构：

[1] Inha Univ, Dept Biomed Sci, Coll Med, Inchon 22212, South Korea

[2] Inha Univ, Coll Med, Hypoxia Related Dis Res Ctr, Inchon 22212, South Korea

[3] Univ Texas Dallas, Dept Biol Sci, Dallas, TX 75080 USA

[4] Inha Univ, Dept Pathol, Coll Med, Inchon 400712, South Korea

[5] Korea Inst Radiol & Med Sci, Div Radiat Effects, Seoul 139706, South Korea

[6] Korea Res Inst Biosci & Biotechnol, Lab Anim Ctr, Daejeon 305806, South Korea

[7] Inha Univ, Dept Polymer Sci & Engn, Inchon 22212, South Korea

[8] Inha Univ, Dept Microbiol, Coll Med, Inchon 22212, South Korea

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

新加坡国家研究基金会;

关键词：

HYPOXIA-INDUCIBLE FACTORS; CARCINOMA-CELL-LINES; DT-DIAPHORASE; NAD(P)H-QUINONE OXIDOREDUCTASE-1; COLON-CANCER; COLORECTAL-CANCER; HIF-ALPHA; FACTOR-I; GENE; EXPRESSION;

D O I：

10.1038/ncomms13593

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1 alpha, 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-1 alpha and inhibits the proteasome-mediated degradation of HIF-1 alpha by preventing PHDs from interacting with HIF-1 alpha. 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-1 alpha expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1 alpha stability in cancers.

引用

页数：14

共 52 条

[1] NQ01 stabilizes p53 through a distinct pathway [J].