A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression

Background Long noncoding RNAs (lncRNAs) are important regulators in tumor progression. However, their biological functions and underlying mechanisms in hypoxia adaptation remain largely unclear. Results Here, we established a correlation between a Chr3q29-derived lncRNA gene and tongue squamous carcinoma (TSCC) by genome-wide analyses. Using RACE, we determined that two novel variants of this lncRNA gene are generated in TSCC, namely LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). RNA-sequencing in 887S or 887L loss-of-function cells identified their common downstream target as Carbonic Anhydrase IX (CA9), a gene known to be upregulated by hypoxia during tumor progression. Mechanistically, our results showed that the hypoxia-augmented 887S and constitutively expressed 887L functioned in opposite directions on tumor progression through the common target CA9. Upon normoxia, 887S and 887L interacted. Upon hypoxia, the two variants were separated. Each RNA recognized and bound to their responsive DNA cis-acting elements on CA9 promoter: 887L activated CA9's transcription through recruiting HIF1 alpha, while 887S suppressed CA9 through DNMT1-mediated DNA methylation. Conclusions We provided hypoxia-permitted functions of two antagonistic lncRNA variants to fine control the hypoxia adaptation through CA9.

Automated summary

This study identified a lncRNA gene related to Chr3q29 in tongue squamous carcinoma and demonstrated how its two variants, 887S and 887L, play opposing roles in tumor progression through the common target CA9. The mechanisms involve the activation of CA9 transcription by 887L through recruiting HIF1 alpha, while 887S suppresses CA9 through DNMT1-mediated DNA methylation. The findings highlight the fine control of hypoxia adaptation through CA9 by these two antagonistic lncRNA variants.