Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
Cancer Res. 2013 Mar 15;73(6):1787-99. doi: 10.1158/0008-5472.CAN-12-0366. Epub 2013 Jan 17.
In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
针对缺氧应激，缺氧诱导因子 (HIF)-1α 是调节基本细胞过程的关键转录因子，其表达水平和活性的升高与大多数恶性肿瘤的不良预后相关。转录因子 Yin Yang 1 (YY1) 是肿瘤抑制因子 p53 的重要负调控因子。然而，YY1 在肿瘤缺氧条件下的作用知之甚少。本文表明，抑制 YY1 可减少缺氧条件下 HIF-1α 的积累及其活性，并因此下调 HIF-1α 靶基因的表达。有趣的是，我们的结果表明，抑制 YY1 下调 HIF-1α 与 p53 无关。功能上，体内实验表明，抑制 YY1 可显著抑制转移性癌细胞的生长和肺定植，并减弱 p53 缺失肿瘤中的血管生成。总之，我们的研究结果揭示了一种新的机制，即 YY1 抑制以 p53 独立的方式破坏缺氧刺激的 HIF-1α 稳定。因此，抑制 YY1 可被视为一种潜在的肿瘤治疗策略，可在不依赖 p53 状态的情况下产生一致的临床效果。
