Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methyladenosine Modifications in Eukaryotic RNAs
3. Writers, Erasers, and Readers in the Coregulation of the Dynamic Adjustment of Methyladenosine Modification
3.1. Writers
3.2. Erasers
3.3. Readers
4. Methyladenosine Modification: An Inseparable Part of Cancers
4.1. Writers in Oncogenesis
4.2. Erasers in Oncogenesis
4.3. Readers in Oncogenesis
4.4. Methyladenosine Modifications in Metastasis
5. Theragnostic Potential of Methyladenosine Modifications in Cancer
5.1. Acting as Diagnostic Markers and Prognostic Predictors
5.2. Conditioning Tumor Microenvironment and Immunotherapy
5.3. Modulating Therapeutic Resistance and Self-Renewal of Cancers
6. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Regulator | Target | Function | Reference |
---|---|---|---|
Writers | |||
METTL3 | m6A | Binding to SAM; catalytic methylation | [26,27] |
METTL14 | m6A | Almost no methyltransferase activity; increases enzyme activity of METTL3 by stabilizing the conformation of METTL3; involved in recognition of bases | [26,27] |
WTAP | m6A | Regulatory factors of MTX of METTL3-METTL14 complex | [28,29] |
KIAA1429 | m6A | Regulatory factors of MTX of METTL3-METTL14 complex | [29] |
TRMT6/TRMT61A complex | m1A | Methyltransferases for mRNA in the cytosol | [6] |
TRMT10C | m1A | Methyltransferases for mitochondrial mRNA | [6] |
PCIF1 | m6Am | Methyltransferases | [30] |
Erasers | |||
FTO | m6A | Catalyzes the reaction of oxidative demethylation of m6A on ssRNAs | [31] |
m6Am | Demethylates m6Am on snRNAs | [16] | |
m1A | Demethylates m1A in RNAs with loop structure and tRNAs | [31] | |
ALKBH5 | m1A | Demethylates specifically m6A on ssRNAs | [20,32] |
Readers | |||
YTHDF1 | m6A | Accelerate the translation process by promoting ribosome binding to target transcripts and increasing translation efficiency | [33] |
YTHDF2 | m6A | Affect mRNA degradation by transporting mRNA with m6A modification to P bodies and other RNA decay sites | [34] |
YTHDF3 | m6A | Promote protein translation in coordination with YTHDF1; accelerate mRNA degradation together with YTHDF2 | [35] |
YTHDC2 | m6A | May involve in the regulation of RNA stability by binding to 5′-3′ exonuclease; affecting translation process by liaising m6A-containing transcripts and ribosomes | [36] |
YTHDF1 | m1A | Promote the translation of transcripts with an m1A modification | [37] |
TYHDF2 | m1A | Accelerate the deg-radiation of modified mRNAs | [37] |
Regulator | Modification | Role in Cancer | Cancer Type | Functional Pathway | References |
---|---|---|---|---|---|
METTL3 | m6A | Oncogenesis | Human cancer cells | EGFR, TAZ | [39] |
METTL3 | m6A | Oncogenesis | Human lung cancer cells | BRD4, eIF3h-dependent | [40] |
METTL3 | m6A | Oncogenesis | Colorectal cancer (CRC) | HK2, SLC2A1, m6A-IGF2BP2/3-dependent | [41] |
METTL3 | m6A | Oncogenesis | CRC | YPEL5, m6A-YTHDF2-dependent | [42] |
METTL3 | m6A | Oncogenesis | Bladder cancer cells | PTEN, pri-miR221/222 | [43] |
METTL3 | m6A | Oncogenesis | Hepatocellular carcinoma (HCC) | UBC9/SUMOylated METTL3/SNAIL axis | [44] |
METTL3 | m6A | Oncogenesis | Glioma | [45,46] | |
METTL3 | m6A | Oncogenesis | Gastric cancer | [47] | |
METTL3 | m6A | Oncogenesis | HCC | [48] | |
METTL3 | m6A | Oncogenesis | Breast cancer (BRCA) | [49] | |
METTL3 | m6A | Oncogenesis | Acute myeloid leukemia (AML) | [50] | |
METTL4 | m6A | Oncogenesis | AML | Self-renewal of leukemia stem cells, initiation of AML | [51] |
METTL4 | m6A | Oncogenesis | BRCA | CXCR4, CYP1B1 | [52] |
METTL4 | m6A | Anti-Oncogenesis | CRC | XIST | [53] |
METTL4 | m6A | Anti-Oncogenesis | CRC | miR375/YAP1 pathway | [54] |
METTL4 | m6A | Anti-Oncogenesis | Gastric cancer | miR-30c-2-3p/AKT1S1 axis | [55] |
METTL4 | m6A | Anti-Oncogenesis | Skin oncogenesis induced by UVB | DDB2 | [56] |
WTAP | m6A | Oncogenesis | HCC | ETS1, HuR/p21/p27-dpendent | [57] |
WTAP | m6A | Oncogenesis | Nasopharyngeal carcinoma | DIAPH1-AS1, MTDH-LASP1 complex, LASP1 | [58] |
TRMT6/TRMT61A | m1A | Oncogenesis | HCC | PPARδ, Cholesterol synthesis, Hedgehog signaling | [59] |
TRMT6/TRMT62A | m1A | Oncogenesis | bladder cancer | Targetome of tRNA fragments, Unfolded protein response, Genes silence | [60] |
FTO | m6A | Oncogenesis | AML | [61,62] | |
FTO | m6A | Oncogenesis | Lung cancer | KRAS ang MZF1 signaling | [63,64] |
FTO | m6A | Oncogenesis | Oral squamous cell carcinoma | eIF4G1 | [65] |
FTO | m6A | Oncogenesis | BRCA | BNIP3, m6A-YTHDF2-dependent | [66] |
FTO | m6A | Oncogenesis | Esophageal squamous Cell carcinoma | LINC00022 | [67] |
FTO | m6A | Anti-Oncogenesis | Pancreatic cancer | Wnt signaling, PJA2 | [68] |
FTO | m6A | Anti-Oncogenesis | Papillary thyroid cancer (PTC) | APOE, m6A-IGF2BP2-dependent | [69] |
ALKBH5 | m6A | Oncogenesis | AML | [70] | |
ALKBH5 | m6A | Anti-Oncogenesis | Pancreatic cancer | PER1, m6A-YTHDF2-dependent | [71] |
YTHDF1 | Oncogenesis | Ovarian cancer | eIF3C | [72] | |
YTHDF1 | Oncogenesis | Gastric cancer | FZD7 | [73] | |
YTHDF2 | Oncogenesis | Lung cancer | AXIN1 | [74] | |
IGF2BP1 | m6A | Oncogenesis | Endometrial cancer | PEG10 mRNA | [75] |
IGF2BP1 | Oncogenesis | Lung, Ovarian and Liver cancer | SRF, FOXK1, PDZ, PDLIM7 | [76] | |
METTL3 | m6A | Metastasis | Gastric cancer | ZMYM1, CtBP/LSD1/CoREST complex | [77] |
METTL3 | Metastasis | Prostate cancer | A2696, USP4, ELAVL1 | [78] | |
METTL3 | Metastasis | CRC | pri-miR-1246, SPRED2/MAPK signaling pathway | [79] | |
METTL3 | Metastasis | Ovarian cancer | pri-miR-1246, CCNG2 pathway | [80] | |
METTL3 | Metastasis | Melanoma cells | MMPs | [81] | |
METTL14 | m6A | Anti-Metastasis | CRC | SOX4, PI3K/Akt signaling | [82] |
METTL14 | Anti-Metastasis | HCC | pri-miR-126, DGCR8 | [83] | |
METTL14 | Anti-Metastasis | Pancreatic cancer | CLK1/SRSF5 pathway | [84] | |
METTL14 | Metastasis | Pancreatic cancer | p53, PERP mRNA | [85] | |
WTAP | Metastasis | Pancreatic cancer | Fak mRNA, Fak-related pathways | [86] | |
FTO | Metastasis | BRCA | miR-181b-3p, ARL5B | [87] | |
FTO | m6A | Metastasis | Gastric cancer | ITGB1 | [88] |
FTO | Anti-Metastasis | CRC | MTA1, IGF2BP2 | [89] | |
AKJBH5 | m6A | Anti-Metastasis | Gastric cancer | PKMYT1, IGF2BP3-m6A-mediated | [90] |
AKJBH5 | Anti-Metastasis | Prostate cancer, CRC and non-small-cell lung cancer | [91,92,93] | ||
YTHDF1 | m6A | Metastasis | HCC (after insufficient radiofrequency ablation) | EGFR | [94] |
YTHDC1 | m6A | Metastasis | Esophageal cancer cells (ESCCs) | MALAT1 | [95] |
YTHDF3 | m6A | Metastasis | BRCA | ST6GALNAC5, GJA1 and EGFR | [96] |
YTHDF2 | Anti-Metastasis | Lung adenocarcinoma | [97] |
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Qu, X.; Zhang, Y.; Sang, X.; Ren, D.; Zhao, H.; Wong, S.T.C. Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer. Cancers 2022, 14, 3195. https://doi.org/10.3390/cancers14133195
Qu X, Zhang Y, Sang X, Ren D, Zhao H, Wong STC. Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer. Cancers. 2022; 14(13):3195. https://doi.org/10.3390/cancers14133195
Chicago/Turabian StyleQu, Xiaolin, Yongqiu Zhang, Xianzheng Sang, Ding Ren, Hong Zhao, and Stephen T. C. Wong. 2022. "Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer" Cancers 14, no. 13: 3195. https://doi.org/10.3390/cancers14133195