Long noncoding RNA LncHIFCAR/MIR31HG is a HIF-1α co-activator driving oral cancer progression

Jing-Wen Shih (), Wei-Fan Chiang, Alexander T. H. Wu, Ming-Heng Wu, Ling-Yu Wang, Yen-Ling Yu, Yu-Wen Hung, Wen-Chang Wang, Cheng-Ying Chu, Chiu-Lien Hung, Chun A. Changou, Yun Yen and Hsing-Jien Kung ()
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Jing-Wen Shih: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University
Wei-Fan Chiang: Chi-Mei Medical Center, Liouying
Alexander T. H. Wu: Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University
Ming-Heng Wu: Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University
Ling-Yu Wang: Comprehensive Cancer Center, University of California at Davis
Yen-Ling Yu: Institute of Molecular and Genomic Medicine, National Health Research Institutes
Yu-Wen Hung: Institute of Molecular and Genomic Medicine, National Health Research Institutes
Wen-Chang Wang: Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University
Cheng-Ying Chu: Research Center of Cancer Translational Medicine, Taipei Medical University
Chiu-Lien Hung: Comprehensive Cancer Center, University of California at Davis
Chun A. Changou: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University
Yun Yen: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University
Hsing-Jien Kung: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Long noncoding RNAs (lncRNAs) have been implicated in hypoxia/HIF-1-associated cancer progression through largely unknown mechanisms. Here we identify MIR31HG as a hypoxia-inducible lncRNA and therefore we name it LncHIFCAR (long noncoding HIF-1α co-activating RNA); we describe its oncogenic role as a HIF-1α co-activator that regulates the HIF-1 transcriptional network, crucial for cancer development. Extensive analyses of clinical data indicate LncHIFCAR level is substantially upregulated in oral carcinoma, significantly associated with poor clinical outcomes and representing an independent prognostic predictor. Overexpression of LncHIFCAR induces pseudo-hypoxic gene signature, whereas knockdown of LncHIFCAR impairs the hypoxia-induced HIF-1α transactivation, sphere-forming ability, metabolic shift and metastatic potential in vitro and in vivo. Mechanistically, LncHIFCAR forms a complex with HIF-1α via direct binding and facilitates the recruitment of HIF-1α and p300 cofactor to the target promoters. Our results uncover an lncRNA-mediated mechanism for HIF-1 activation and establish the clinical values of LncHIFCAR in prognosis and potential therapeutic strategy for oral carcinoma.

Date: 2017
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DOI: 10.1038/ncomms15874

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