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

Abstract

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 HIF1α, 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.

LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond

“…In lung adenocarcinoma (LUAD), lncRNA HAGLR was identified as a tumor suppressor by recruiting DNMT1 to the promoter of E2F1 to inhibit tumor growth [ 58 ]. A recent study revealed a more complex scenario, in which the authors identified two novel variants of lncRNA LINC00887 , and showed that the short form variant suppressed Carbonic Anhydrase IX ( CA9 ) by recruiting DNMT1 to its promoter, while the long-form variant activated CA9 's transcription via interacting with HIF1α [ 45 ]. The two variants were supposed to differentially respond to hypoxia and oppositely control the progression of tongue squamous carcinoma [ 45 ].…”

Alteration of RNA m6A methylation mediates aberrant RNA binding protein expression and alternative splicing in condyloma acuminatum

“…There are two novel variants of lncRNA LINC00887 in tongue squamous carcinoma, namely, LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). 887L activated carbonic anhydrase IX transcription by recruiting HIF1 α , while 887S suppressed carbonic anhydrase IX through DNMT1-mediated DNA methylation ( Shen et al, 2021 ). Herein, we confirmed that two apoptosis-related genes, RASAL2 ( Koh et al, 2021 ; Xiong et al, 2021 ) and YWHAZ ( Nishimura et al, 2013 ; Zhang et al, 2021 ) were associated with 5ASS ASEs in both our RNA-sequencing data and RT-qPCR validation data.…”

Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy

“…This indicates that there is a complex multifactorial mechanism behind regulation of CAIX and CAXII expression. Although HIF-1 plays the major role in regulation of expression of CAIX and CAXII, it is far from the only protein involved as other mechanisms, including MORC2 and non-coding RNA, were reported on recently [ 66 , 67 , 68 , 69 , 70 ]. Additionally, di Fiore et al recently reported on the currently known posttranslational modification mechanisms of CAIX and CAXII and stated that these modifications partly have a yet unknown impact on the function of CAIX/CAXII, indicating that there may also be fluctuation in CAIX/CAXII efficacy present on a protein level [ 71 ].…”