Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Mol Cell. 2014 Jan 9;53(1):88-100. doi: 10.1016/j.molcel.2013.11.004. Epub 2013 Dec 5.
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-1α-induced lincRNA-p21 is able to bind HIF-1α and VHL and thus disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the existence of a positive feedback loop between HIF-1α 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.
缺氧长期以来与瓦博格效应有关，但潜在机制在很大程度上仍不清楚。目前也不清楚 lncRNA 是否参与了缺氧对瓦博格效应的贡献。在这里，我们表明 lincRNA-p21 是一种缺氧反应性 lncRNA，对缺氧增强的糖酵解至关重要。缺氧/HIF-1α 诱导的 lincRNA-p21 能够结合 HIF-1α 和 VHL，从而破坏 VHL-HIF-1α 相互作用。这种解偶联减弱了 VHL 介导的 HIF-1α 泛素化，并导致 HIF-1α 积累。这些数据表明 HIF-1α 和 lincRNA-p21 之间存在正反馈回路，促进缺氧下的糖酵解。lincRNA-p21 在小鼠异种移植模型中促进肿瘤生长的能力得到了验证。总之，这些发现表明 lincRNA-p21 是瓦博格效应调节的重要参与者，也暗示 lincRNA-p21 是癌症有价值的治疗靶点。
