Long Noncoding Rna Lnchifcar/Mir31hg Is A Hif-1 Alpha Co-Activator Driving Oral Cancer Progression

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-1 alpha co-activating RNA); we describe its oncogenic role as a HIF-1 alpha 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-1 alpha transactivation, sphere-forming ability, metabolic shift and metastatic potential in vitro and in vivo. Mechanistically, LncHIFCAR forms a complex with HIF-1 alpha via direct binding and facilitates the recruitment of HIF-1 alpha 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.