Reciprocal Regulation of HIF-1α and LincRNA-p21 Modulates the Warburg Effect
Reciprocal Regulation of HIF-1α and LincRNA-p21 Modulates the Warburg Effect
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HIF-1 α 和 LincRNA-p21 的相互调节调节 Warburg 效应
DOI：
10.1016/j.molcel.2013.11.004
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发表时间：
2014-01-01
期刊：
影响因子：
16
通讯作者：
Wu, Mian
中科院分区：
文献类型：
--
作者：
Yang, Fan;Zhang, Huafeng;Wu, Mian
长期以来，缺氧一直与瓦尔堡效应有关，但其潜在机制仍不清楚。也不知道lncRNA是否参与缺氧对瓦尔堡效应的贡献。在这里，我们表明lincRNA-p21是一种缺氧反应性lncRNA，是缺氧增强糖酵解所必需的。缺氧/HIF-1 α诱导的lincRNA-p21能够结合HIF-1 α和VHL，从而破坏VHL-HIF-1 α相互作用。这种解离减弱VHL介导的HIF-1 α泛素化，并导致HIF-1 α积累。这些数据表明HIF-1 α和lincRNA-p21之间存在促进缺氧条件下糖酵解的正反馈环。在小鼠异种移植模型中验证了lincRNA-p21促进肿瘤生长的能力。总之，这些发现表明lincRNA-p21在调节瓦尔堡效应中是重要的参与者，并且还暗示lincRNA-p21作为癌症的有价值的治疗靶标。
Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. Hypoxia/HIF-1 alpha-induced lincRNA-p21 is able to bind HIF-1 alpha and VHL and thus disrupts the VHL-HIF-1 alpha interaction. This disassociation attenuates VHL-mediated HIF-1 alpha ubiquitination and causes HIF-1 alpha accumulation. These data indicate the existence of a positive feedback loop between HIF-1 alpha and lincRNA-p21 that promotes glycolysis under hypoxia. The ability of lincRNA-p21 to promote tumor growth is validated in mouse xenograft models. Together, these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.