Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction.
Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction.
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DOI：
10.3390/ijms15057974
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发表时间：
2014-05-07
影响因子：
5.6
通讯作者：
Shang H
中科院分区：
文献类型：
--
作者：
Guo Y;Meng X;Ma J;Zheng Y;Wang Q;Wang Y;Shang H
宫颈癌仍然是全世界妇女癌症死亡的主要原因之一，特别是在发展中国家。癌细胞的一个主要代谢特征是即使在有足够氧气存在的情况下也消耗大量葡萄糖并通过糖酵解获得更多能量，这被称为瓦尔堡效应，其可被缺氧放大。高危亚型HPV 16早期癌蛋白E6通过与多种细胞因子相互作用促进宿主细胞永生化和转化。缺氧诱导因子1α（HIF-1α）是一种广泛表达的转录调节因子，参与诱导许多与血管生成和肿瘤生长相关的基因，HPV E6可使其表达水平显著升高。HIF-1α是von Hippel-Lindau肿瘤抑制因子（VHL）作为E3连接酶降解的最知名靶标。本研究发现HPV 16 E6通过阻断HIF-1α与VHL的结合，促进缺氧诱导的瓦尔堡效应。这种解离减弱了VHL介导的HIF-1α泛素化并导致HIF-1α积累。这些结果表明，癌蛋白E6在调节瓦尔堡效应中起主要作用，并可能成为HPV相关癌症的有价值的治疗靶点。
Cervical cancer is still one of the leading causes of cancer deaths in women worldwide, especially in the developing countries. It is a major metabolic character of cancer cells to consume large quantities of glucose and derive more energy by glycolysis even in the presence of adequate oxygen, which is called Warburg effect that can be exaggerated by hypoxia. The high risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. Hypoxia-inducible factor 1α (HIF-1α), a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth, is highly increased by HPV E6. HIF-1α is a best-known target of the von Hippel-Lindau tumor suppressor (VHL) as an E3 ligase for degradation. In the present work, we found that HPV16 E6 promotes hypoxia induced Warburg effect through hindering the association of HIF-1α and VHL. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These results suggest that oncoprotein E6 plays a major role in the regulation of Warburg effect and can be a valuable therapeutic target for HPV-related cancer.
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影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
影响因子：
64.5
作者：
SCHEFFNER, M;HUIBREGTSE, JM;HOWLEY, PM
通讯作者：
HOWLEY, PM
影响因子：
3.7
作者：
Rodolico V;Arancio W;Amato MC;Aragona F;Cappello F;Di Fede O;Pannone G;Campisi G
通讯作者：
Campisi G
影响因子：
6
作者：
Talks, KL;Turley, H;Harris, AL
通讯作者：
Harris, AL
影响因子：
4.8
作者：
Semenza, GL;Jiang, BH;Giallongo, A
通讯作者：
Giallongo, A