The relationship between the network of non-coding RNAs-molecular targets and N6-methyladenosine modification in tumors of urinary system

Abstract

N6-methyladenosine (m6A) methylation, a prevalent eukaryotic post-transcriptional modification, is involved in multiple biological functions, including mediating variable splicing, RNA maturation, transcription, and nuclear export, and also is vital for regulating RNA translation, stability, and cytoplasmic degradation. For example, m6A methylation can regulate pre-miRNA expression by affecting both splicing and maturation. Non-coding RNA (ncRNA), which includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), does not encode proteins but has powerful impacts on transcription and translation. Conversely, ncRNAs may impact m6A methylation by affecting the expression of m6A regulators, including miRNAs targeting mRNA of m6A regulators, or lncRNAs, and circRNAs, acting as scaffolds to regulate transcription of m6A regulatory factors. Dysregulation of m6A methylation is common in urinary tumors, and the regulatory role of ncRNAs is also important for these malignancies. This article provides a systematic review of the role and mechanisms of action of m6A methylation and ncRNAs in urinary tumors.

Fig. 1. Functions of m6A regulators.

M6A “writers” include METTL3, METTL14/16, WTAP, VIRMA, Hakai, Virilizer, ZC3H13, RBM15, and RBM15B; M6A “erasers” include FTO and ALKBHs; M6A “readers” include YTHDF1, YTHDF2, YTHDF3, YTHDC1, HNRNPC, HNRNPA2B1, HNRNPG, and IGF2BP1/2/3. Their functions are involved in RNA degradation, stabilization, and translation, pre-mRNA splicing, and transport, etc.

Fig. 2. The interactions between m6A methylation and ncRNAs in PCa.

A METTL3 bound to DGCR8, identified the m6A site on pri-miR-182, promoted its maturation, and ultimately accelerated PCa invasion and migration. B VIRMA stabilized the expression of lncRNA CCAT1/CCAT2 by targeting its m6A site and promoted the proliferation and invasion of PCa. C METTL3 stabilized the expression of lncRNA SNHG7 through m6A modification, facilitated its binding with SRSF1, and ultimately increased the expression of c-MYC, thus promoting the proliferation and glycolysis of PCa. D METTL3 promoted the expression of lncRNA MALAT1 through m6A modification, thereby affecting the PI3K/AKT pathway and promoting the proliferation and invasion of PCa. E LncRNA NEAT1 can recruit CYCLINL1 and CDK19 to the promoter region of RUNX2 through m6A modification sites and promote PCa bone metastasis. F METTL3 can mediate lncRNA PCAT6 m6A modification, and then bind IGF2BP2 and IGF1R mRNA to form a complex to stabilize its expression, and ultimately promote PCa bone metastasis. G WTAP formed a complex with circPDE5A, bound to EIF3C, and ultimately down-regulated its expression, promoting PCa migration and invasion.

Fig. 3. The interactions between m6A methylation and ncRNAs in BCa.

A METTL3 bound to DGCR8, identified the m6A site on pri-miR-221/222, promoted its maturation, and ultimately inhibited the expression of PTEN to stimulate the proliferation of BCa. B METTL3 promoted the maturation of pri-miR-146a-5p, and then affected the NUMB/NOTCH2 pathway to inhibit BCa apoptosis. C FTO decreased the expression of miR-576 by removing m6A methylation on miR-576, and finally promoted the expression of CDK6, and stimulated the proliferation, invasion, and metastasis of BCa. D CircPTPRA bound to IGF2BP1 and blocked its binding to MYC/FSCN1, leading to a decrease in its expression level and promoting BCa apoptosis. E MiR-5581-3p attenuated BCa migration and proliferation by acting as a sponge to inhibit FTO expression. F Circ0008399 promoted the methylation of m6A on TNFAIP3 mRNA by binding to WTAP/METTL3/METTL14 complex, and eventually promoted its expression, leading to BCa apoptosis.

Fig. 4. The interactions between m6A methylation and ncRNAs in RCC.

A METTL3 bound to lncRNA NEAT1 to induce its m6A methylation and promote its expression, ultimately boosting the proliferation and migration of RCC. B LncRNA DMDRMR promoted the proliferation and migration of RCC by binding to IGF2BP3 and CDK4. C METTL14 can bind to lncRNA NEAT1_1 to induce m6A methylation, and then combine with YTHDF2 to inhibit its expression, thereby restraining the growth and metastasis of RCC. D METTL14 can bind to lncRNA LSG1 to induce m6A methylation, and then combine with YTHDC1 to inhibit its expression, thereby retarding the metastasis of RCC. E YTHDF2 can inhibit circPOLR2A expression by binding to its m6A modification sites. F YTHDC1 bound to the m6A site on circMET, promoted its transport to the cytoplasm, and then bound to YTHDF2, inhibited the expression of CDKN2A, and finally promoted the proliferation of RCC. G MiR-155 inhibited RCC apoptosis by targeting FTO expression. H MiR-501-3p inhibited RCC proliferation by targeting WTAP and restraining its expression. (I) CircPLIN2 can promote the expression of c-MYC by binding to IGF2BPs, and finally promote the proliferation, invasion, and migration of RCC.