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A lncRNA coordinates with Ezh2 to inhibit HIF-1α transcription and suppress cancer cell adaption to hypoxia.
Oncogene ( IF 8 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41388-019-1123-9
Xingwen Wang 1 , Yudong Wang 1 , Li Li 2 , Xuting Xue 1 , Hui Xie 3 , Huaxing Shi 4 , Ying Hu 1, 5
Affiliation  

Hypoxia is a salient feature of the tumor microenvironment. HIF-1α is a master regulator of hypoxic adaption. The polycomb repressor complex 2 (PRC2) molecule Ezh2 is known to play roles in essential cellular processes of cell fate decisions. However, how PRC2-mediated epigenetic dynamic changes take part in hypoxic adaption is not completely understood. Recently, we identified a long non-coding RNA (lncRNA) named HITT (HIF-1α inhibitor at translation levels) that plays roles in modulating hypoxia-mediated angiogenesis and tumor growth in vivo. In this study, we reveal an important activity of HITT in evading hypoxia-induced apoptosis by coordinating with PRC2 activity to regulate HIF-1α transcription. Genetic or chemical inhibition of PRC2 significantly elevates HIF-1α mRNA levels. The occupancy of Ezh2 and its substrate H3K27me3 on the HIF-1α promoter is detected under normoxia, and is reduced by hypoxia. Restoring hypoxia-inhibited HITT expression rescues the association between Ezh2/H3K27me3 and the HIF-1α promoter, which also simultaneously abrogates hypoxia-induced HIF-1α mRNA transcription. Further mechanistic studies revealed that HITT inhibits HIF-1α transcription by guiding Ezh2 through the formation of an RNA-DNA triplex with the HIF-1α promoter. Importantly, HITT/Ezh2-regulated HIF-1α transcription leads to alerted HIF-1α protein output and elicits a significant effect to evade hypoxia-induced apoptosis. Importantly, a close association between HIF-1α mRNA and HITT was further verified in human colon cancer tissues in vivo. Collectively, these findings suggest a model for the epigenetic regulation of hypoxia-induced HIF-1α transcription modulated by lncRNA HITT, which provides important insights into how tumor cells sense and adapt to hypoxic stress.

中文翻译:

一个 lncRNA 与 Ezh2 协同抑制 HIF-1α 转录并抑制癌细胞对缺氧的适应。

缺氧是肿瘤微环境的一个显着特征。HIF-1α 是缺氧适应的主要调节剂。已知多梳阻遏复合物 2 (PRC2) 分子 Ezh2 在细胞命运决定的基本细胞过程中发挥作用。然而,PRC2 介导的表观遗传动态变化如何参与缺氧适应尚不完全清楚。最近,我们发现了一种名为 HITT(翻译水平的 HIF-1α 抑制剂)的长链非编码 RNA (lncRNA),它在体内调节缺氧介导的血管生成和肿瘤生长中发挥作用。在这项研究中,我们揭示了 HITT 通过与 PRC2 活性协调调节 HIF-1α 转录来逃避缺氧诱导的细胞凋亡的重要活性。PRC2 的遗传或化学抑制显着提高了 HIF-1α mRNA 水平。在常氧条件下检测到 Ezh2 及其底物 H3K27me3 在 HIF-1α 启动子上的占据,并在缺氧条件下减少。恢复缺氧抑制的 HITT 表达可以挽救 Ezh2/H3K27me3 和 HIF-1α 启动子之间的关联,这也同时消除了缺氧诱导的 HIF-1α mRNA 转录。进一步的机制研究表明,HITT 通过引导 Ezh2 通过与 HIF-1α 启动子形成 RNA-DNA 三链体来抑制 HIF-1α 转录。重要的是,HITT/Ezh2 调节的 HIF-1α 转录导致 HIF-1α 蛋白输出的警报,并引发显着影响逃避缺氧诱导的细胞凋亡。重要的是,在体内人结肠癌组织中进一步证实了 HIF-1α mRNA 和 HITT 之间的密切关联。集体,
更新日期:2019-11-30
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