A novel N6-methyladenosine (m6A)-dependent fate decision for the lncRNA THOR

Abstract

Previous studies have revealed the critical roles of the N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in cancers, but the relationship between the oncogenic role of the lncRNA THOR (a representative of cancer/testis lncRNAs) and m6A modification remains unclear. Here, we show that the internal m6A modification of the lncRNA THOR via an m6A-reader-dependent modality regulates the proliferation of cancer cells. Our findings demonstrated that the loss of the lncRNA THOR inhibits the proliferation, migration, and invasion of cancer cells in vitro and in vivo. In addition, m6A is highly enriched on lncRNA THOR transcripts, which contain GA (m6A) CA, GG (m6A) CU, and UG (m6A) CU sequence motifs. RIP-qRT-PCR and RNA pull-down assay results revealed that the specific m6A readers YTHDF1 and YTHDF2 can read the m6A motifs and regulate the stability of the lncRNA THOR (stabilization and decay). These m6A-dependent RNA-protein interactions can maintain the oncogenic role of the lncRNA THOR. Collectively, these findings highlight the critical role of the m6A modification in oncogenic lncRNA THOR and reveal a novel long non-coding RNA regulatory mechanism, providing a new way to explore RNA epigenetic regulatory patterns in the future. Recently, the new field of "RNA epigenetics" has been booming 14,15 , and N6-methyladenosine (m6A) has been identified as a post-transcriptional regulatory mark in multiple RNA species, including messenger RNAs (mRNAs) 1,2,16 , transfer RNAs (tRNAs) 3,4,17-20 , ribosomal RNAs (rRNAs) 21 , small nuclear RNA 22 , small non-coding RNAs (sncRNAs) 23 , and lncRNAs 16,24. It has been reported that the m6A RNA modification is conferred by methyltransferases (writers), such as methyltransferaselike 3 (METTL3), forming the catalytic core of the m6A methyltransferase complex 25-28. In addition, the biological function of m6A is mediated through the recognition of the m6A site by m6A "readers" 1,29,30 , such as the YT521-B homology (YTH) family, including YTH domain

METTL14 Suppresses Pyroptosis and Diabetic Cardiomyopathy by Down-Regulating TINCR lncRNA

“…It is reported that m6A process was closely associated with lncRNA processing (14). By performing GSEA analysis, we revealed that METTL14 was involved in the process and degradation of ncRNAs (Figure 5A).…”

METTL3 Regulates Ossification of the Posterior Longitudinal Ligament via the lncRNA XIST/miR-302a-3p/USP8 Axis

“…Coker et al found that METTL3 promotes m 6 A modification of XIST, which is recognized by m 6 A reader YTHDC1, leading to X chromosome inactivation ( Coker et al, 2020 ). Liu et al indicated that METTL3 promotes m 6 A modification of lncRNA THOR and cancer cell proliferation ( Liu et al, 2020 ). Another study indicated that lncRNA pncRNA-D suppresses cyclin D1 and arrests cell cycle through RNA m 6 A modification ( Yoneda et al, 2020 ).…”

The Emerging Clinical Application of m6A RNA Modification in Inflammatory Bowel Disease and Its Associated Colorectal Cancer

“…Specific m6A readers YTHDF1 and YTHDF2 can read the highly enriched m6A motif on lncRNA Thor transcripts, regulate its stability, and thus maintain the carcinogenic effect. 46 Interestingly, the two studies of He et al 47 and Chen et al 48 respectively confirmed that ALKBH5 played two opposite effects of promoting cancer and inhibiting cancer in different cancers by regulating different lncRNA levels through demethylation. ALKBH5 inhibits the progression of pancreatic cancer by demethylation of lncRNA KCNK15-AS1, while the up-regulation of lncRNA PVT1 mediated by ALKBH5 promotes the proliferation of osteosarcoma cells in vitro and tumor growth in vivo.…”