Distinct Hypoxia-Responsive lncRNA Variants Oppositely Control Tumorigenesis Via Interplay on CA9

The biological consequences of alternative promoter (AP) selection remain largely unclear. Here, we identify two AP generated long noncoding RNAs (lncRNAs) from chromosome 3q29, namely 887L and 887S, which are differentially modulated by hypoxia in tumor cells. Through either recruiting HIF1α or DNMT1 to the target gene’s promoter, the hypoxia-independent 887L and hypoxia/HIF2α-induced 887S antagonistically regulate the expression and pH modulating activity of oncogene carbonic anhydrase 9 (CA9) respectively and play opposite roles in tumorigenesis. Moreover, 887L disrupts the association between DNMT1 and the CpG site by sequestering 887S from chromatin. Therefore, our data provide a delicate regulatory network on a crucial oncogene via two lncRNA variants, transcriptional activator HIFα and epigenetic factor DNMT1 to influence the tumorigenesis.