RNA modifications in cancer

Abstract

Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m⁶A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m⁶A RNA methylation. In this review, we focus on several important RNA modifications including m¹A, m⁵C, m⁷G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.

Fig. 1

Chemical structures and regulatory enzymes for common RNA modifications

Fig. 2. Roles of m¹A and m⁵C modifications in cancer.

a Role of m¹A modifications in cancer. m¹A on mRNA (e.g., CSF-1, COL1A1/2) affects tumour invasion and metastasis by regulating mRNA stability. m¹A on tRNA affects tumourigenesis and apoptosis by promoting the translation of downstream target genes (such as PPARδ) and inhibiting the generation of tDRs. b Role of m⁵C modifications in cancer. m⁵C modifications on oncogenes (FTH1/FTL, PKM2, TEAD1, E2F5, YY1, RCC2, FOXC2, HDGF, KRT13, PIK3R1, PCYT1A and GRB2) enhance mRNA stability or translation, and then inhibit ferroptosis and promote tumour cell metabolic reprogramming, proliferation, invasion, and migration. The m⁵C modification of CDKN1C mRNA promotes CDKN1C degradation and induces cell proliferation. The m⁵C modifications of lncRNA (lncRNA H19 and lncRNA NKILA) enhance their stability, which further influences tumourigenesis and cancer progression. m⁵C on mRNA of DNA:RNA hybrids at DNA damage sites promotes DNA damage repair by recruiting DNA repair proteins and regulating the decomposition of R-loop.

Fig. 3. Role of m⁷G, 2′-O-Me, and Ψ modifications in cancer.

a Role of m⁷G modifications in cancer. mRNA (such as cyclin D1) cap methylation promotes mRNA translation and affects tumourigenesis. The increase of m⁷G modification on tRNA upregulates the translation of some oncogenes (e.g., EGFR/EFEMP1, RPTOR and relevant genes in PI3K/AKT/mTOR and WNT/β-catenin signalling pathways) to promote tumourigenesis, proliferation, invasion, and metastasis, and inhibit cell death. The m⁷G modification on miR-149-3p upregulates miRNA levels and inhibits the expression of oncogene S100A4. The m⁷G modification on let-7e pri-miRNA promotes its processing and further represses some genes associated with migration. b Role of 2′-O-Me modifications in cancer. Upregulation of C/D-box snoRNAs (e.g., SNORD14D, SNORD35A, SNORD42A, SNORD12C and SNORD78) in tumours enhances the translation of some oncogenes (e.g., VEGF, XIAP, EIF4A3 and LAMC2) by inducing 2′-O-Me modifications of rRNA. 2′-O-Me modification of miR-21-5p enhances miRNA stability and interaction with AGO2, which inhibits the expression of oncogene PDCD4 and ultimately promotes apoptosis. c Role of Ψ modifications in cancer. Ψ modifications on ribosomal protein mRNAs (e.g., RPL10A, RPL22L1, RPL34 and RPS3) enhance RNA stability, leading to increased ribosomal protein abundance, and promoting tumour cell proliferation. Ψ modifications on rRNA and tRNA affect tumourigenesis and cancer progression by regulating translation. The Ψ modifications on rRNA enhance IRES-dependent translation of the antioncogene p27 to suppress tumours, and also affects tumourigenesis by enhancing translation efficiency of ribosomes, improving translation fidelity, and enhancing mitochondrial function. Ψ modifications on tRNA affect tumourigenesis and cancer progression by promoting the production of 5′ tRFs or by inhibiting the translation of target genes (e.g., TYK2).

Fig. 4. Role of A-to-I editing in cancer.

a Role of A-to-I editing on mRNA in cancer. In mRNA, A-to-I editing regulates the expression of mRNA (such as GM2A, DHFR, SLC22A3, and CDC14B) to affect tumourigenesis. Meanwhile, A-to-I editing affects protein stability, binding to partners, and subcellular localisation through facilitating conformational changes in proteins such as CDK13, GLI1, Gabra3, AZIN1, COPA, BLCAP and IGFBP7 to regulate cell cycle, angiogenesis, proliferation, invasion, and migration. b A-to-I editing affects tumourigenesis and cancer progression by affecting pri-miRNA processing and maturation, and downstream targets of miRNA. For example, edited pri-miR-142-3p hinders its own processing and maturation, leading to upregulation of STAU1 and ultimately inhibiting cell migration and invasion. Unedited miR-376a* and miR-589-3p and edited miR-200b promote tumourigenesis, while edited miR-376a* and miR-589-3p and unedited miR-200b display tumour suppressor effects. Edited miR378a-3p and miR-379-5p suppressed the expression of oncogenes PAPVA and CD97, respectively. Edited miR-455-5p blocked the inhibitory effect of wild-type miR-455-5p on the tumour suppressor gene CPEB1.