NQO1 inhibits proteasome-mediated degradation of HIF-1α.
NQO1 inhibits proteasome-mediated degradation of HIF-1α.
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DOI：
10.1038/ncomms13593
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发表时间：
2016-12-14
影响因子：
16.6
通讯作者：
Park, Heon Joo
中科院分区：
文献类型：
--
作者：
Oh, Eun-Taex;Kim, Jung-whan;Kim, Joon Mee;Kim, Soo Jung;Lee, Jae-Seon;Hong, Soon-Sun;Goodwin, Justin;Ruthenborg, Robin J.;Jung, Myung Gu;Lee, Hae-June;Lee, Chul-Ho;Park, Eun Sung;Kim, Chulhee;Park, Heon Joo
NQO 1的过表达与包括乳腺癌、结肠癌、宫颈癌、肺癌和胰腺癌在内的人类癌症的不良预后相关。然而，NQO 1的促肿瘤发生能力的分子机制尚未完全阐明。在这里，我们展示了NQO 1在稳定HIF-1α中的一种以前未描述的功能，HIF-1 α是一种氧稳态的主要转录因子，与癌症的生存、增殖和恶性进展有关。我们证明NQO 1直接与HIF-1α的氧依赖性结构域结合，并通过阻止PHDs与HIF-1α相互作用来抑制蛋白酶体介导的HIF-1α降解。NQO 1在人结直肠癌和乳腺癌细胞系中的敲低抑制HIF-1信号传导和肿瘤生长。与NQO 1的促肿瘤发生功能一致，高NQO 1表达水平与HIF-1α表达增加和结直肠癌患者生存率低相关。这些结果共同揭示了NQO 1在调节癌症中HIF-1α稳定性的氧敏感机制中的功能。 肿瘤中氧化还原酶NQO 1水平升高与预后不良有关，但这如何导致癌症尚不清楚。在这里，作者发现NQO 1与PHD蛋白竞争，导致缺氧诱导的转录因子HIF-1α的稳定。
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. Elevated levels of the oxidoreductase NQO1 in tumours are associated with poor prognosis but how this contributes to cancer is poorly understood. Here, the authors find that NQO1 competes with PHD proteins, resulting in the stabilization of the hypoxia induced transcription factor HIF-1α.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
11.2
作者：
Dang, DT;Chen, F;Dang, LH
通讯作者：
Dang, LH
影响因子：
5.3
作者：
Chan, DA;Sutphin, PD;Giaccia, AJ
通讯作者：
Giaccia, AJ
影响因子：
16
作者：
Liu, Ye V.;Baek, Jin H.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
DOI：
10.1093/jnci/91.22.1940
发表时间：
1999-11-17
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Kelland, LR;Sharp, SY;Workman, P
通讯作者：
Workman, P