1. Academic Validation
  2. A lncRNA coordinates with Ezh2 to inhibit HIF-1α transcription and suppress cancer cell adaption to hypoxia

A lncRNA coordinates with Ezh2 to inhibit HIF-1α transcription and suppress cancer cell adaption to hypoxia

  • Oncogene. 2020 Feb;39(9):1860-1874. 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 5 6
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China.
  • 2 The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
  • 3 State Key Laboratory of Robotics and Systems, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China.
  • 4 School of Computer Science and Technology, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China.
  • 5 School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China. huying@hit.edu.cn.
  • 6 Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, 518055, China. huying@hit.edu.cn.
Abstract

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.

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