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

Oncogene volume 39, pages 1860–1874 (2020)Cite this article

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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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References

  1. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357:aal2380–2390.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Piunti A, Shilatifard A. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science. 2016;352:aad9780.

    Article  PubMed  CAS  Google Scholar 

  3. Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ. Role of EZH2 histone methyltrasferase in melanoma progression and metastasis. Cancer Biol Ther. 2016;17:579–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.

    Article  CAS  PubMed  Google Scholar 

  5. Collett K, Eide GE, Arnes J, Stefansson IM, Eide J, Braaten A, et al. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res. 2006;12:1168–74.

    Article  CAS  PubMed  Google Scholar 

  6. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.

    Article  CAS  PubMed  Google Scholar 

  7. Comet I, Riising EM, Leblanc B, Helin K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer. 2016;16:803–10.

    Article  CAS  PubMed  Google Scholar 

  8. Holoch D, Margueron R. Mechanisms regulating PRC2 recruitment and enzymatic activity. Trends Biochem Sci. 2017;42:531–42.

    Article  CAS  PubMed  Google Scholar 

  9. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.

    Article  CAS  PubMed  Google Scholar 

  10. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47:199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol cell. 2011;43:904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature. 2012;482:339–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322:750–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011;1:391–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol. 2010;22:177–80.

    Article  CAS  PubMed  Google Scholar 

  19. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11:393–410.

    Article  CAS  PubMed  Google Scholar 

  20. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol cell. 2010;40:294–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 2011;14:191–201.

    Article  CAS  PubMed  Google Scholar 

  22. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.

    Article  CAS  PubMed  Google Scholar 

  23. Perez-Perri JI, Acevedo JM, Wappner P. Epigenetics: new questions on the response to hypoxia. Int J Mol Sci. 2011;12:4705–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen S, Chen JZ, Zhang JQ, Chen HX, Yan ML, Huang L, et al. Hypoxia induces TWIST-activated epithelial-mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice. Cancer Lett. 2016;383:73–84.

    Article  CAS  PubMed  Google Scholar 

  25. Wang X, Li L, Zhao K, Lin Q, Li H, Xue X, et al. A novel LncRNA HITT forms a regulatory loop with HIF-1alpha to modulate angiogenesis and tumor growth. Cell Death Differ. 2019.

  26. Li Z, Hou P, Fan D, Dong M, Ma M, Li H, et al. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ. 2017;24:59–71.

    Article  PubMed  CAS  Google Scholar 

  27. Buske FA, Bauer DC, Mattick JS, Bailey TL. Triplexator: detecting nucleic acid triple helices in genomic and transcriptomic data. Genome Res. 2012;22:1372–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kinnaird A, Zhao S, Wellen KE, Michelakis ED. Metabolic control of epigenetics in cancer. Nat Rev Cancer. 2016;16:694–707.

    Article  CAS  PubMed  Google Scholar 

  30. Pang B, Zheng XR, Tian JX, Gao TH, Gu GY, Zhang R, et al. EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1alpha signaling. Oncotarget. 2016;7:45134–43.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mahara S, Lee PL, Feng M, Tergaonkar V, Chng WJ, Yu Q. HIFI-alpha activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer. Proc Natl Acad Sci USA. 2016;113:E3735–3744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, et al. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Investig. 2015;125:4375–90.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73.

    Article  CAS  PubMed  Google Scholar 

  35. Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, et al. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med. 2005;16:349–53.

    CAS  PubMed  Google Scholar 

  36. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012;18:298–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013;23:839–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, et al. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell. 2005;121:425–36.

    Article  CAS  PubMed  Google Scholar 

  39. Campbell S, Ismail IH, Young LC, Poirier GG, Hendzel MJ. Polycomb repressive complex 2 contributes to DNA double-strand break repair. Cell Cycle. 2013;12:2675–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Battistelli C, Cicchini C, Santangelo L, Tramontano A, Grassi L, Gonzalez FJ, et al. The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene. 2017;36:942–55.

    Article  CAS  PubMed  Google Scholar 

  41. Pruszko M, Milano E, Forcato M, Donzelli S, Ganci F, Di Agostino S, et al. The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1. EMBO Rep. 2017;18:1331–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Developmental Cell. 2013;24:206–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, et al. MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat Commun. 2015;6:7743.

    Article  CAS  PubMed  Google Scholar 

  44. Orphanides G, Reinberg D. A unified theory of gene expression. Cell. 2002;108:439–51.

    Article  CAS  PubMed  Google Scholar 

  45. Cheng YH, Chuang CN, Shen HJ, Lin FM, Wang TF. Three distinct modes of Mec1/ATR and Tel1/ATM activation illustrate differential checkpoint targeting during budding yeast early meiosis. Mol Cell Biol. 2013;33:3365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Belaiba RS, Bonello S, Zahringer C, Schmidt S, Hess J, Kietzmann T, et al. Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. Mol Biol Cell. 2007;18:4691–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sperandio S, Fortin J, Sasik R, Robitaille L, Corbeil J, de Belle I. The transcription factor Egr1 regulates the HIF-1alpha gene during hypoxia. Mol Carcinog. 2009;48:38–44.

    Article  CAS  PubMed  Google Scholar 

  48. Wen Y, Zhou X, Lu M, He M, Tian Y, Liu L, et al. Bclaf1 promotes angiogenesis by regulating HIF-1alpha transcription in hepatocellular carcinoma. Oncogene. 2019;38:1845–59.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang Y, He Q, Hu Z, Feng Y, Fan L, Tang Z, et al. Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol. 2016;23:522–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was funded by the National Nature Science Foundation of China (No. 31301131, 31741084 and 31871389) and Basic Science Fundation of Science and technology innovation Commission in Shenzhen (No. JCYJ20170811154452255).

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Authors and Affiliations

  1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China

    Xingwen Wang, Yudong Wang, Xuting Xue & Ying Hu

  2. The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China

    Li Li

  3. State Key Laboratory of Robotics and Systems, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China

    Hui Xie

  4. School of Computer Science and Technology, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China

    Huaxing Shi

  5. Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, 518055, China

    Ying Hu

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Wang, X., Wang, Y., Li, L. et al. A lncRNA coordinates with Ezh2 to inhibit HIF-1α transcription and suppress cancer cell adaption to hypoxia. Oncogene 39, 1860–1874 (2020). https://doi.org/10.1038/s41388-019-1123-9

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