N6-methyladenosine Modification of Noncoding RNAs: Mechanisms and Clinical Applications in Cancer
Abstract
:1. Introduction
2. Regulators of m6A
2.1. m6A Writers
2.2. m6A Erasers
2.3. m6A Readers
2.3.1. YT521-B Homology (YTH) Domain Family
2.3.2. Heterogeneous Nuclear Ribonucleoproteins
3. m6A-Modification and ncRNA
3.1. m6A-Modification in miRNA
3.2. m6A-Modification in lncRNA
3.3. m6A-Modification in circRNA
4. Clinical Applications of m6A for ncRNA in Cancer
4.1. Role of ncRNA Methylation in Predicting Prognosis of Cancer
4.2. m6A Inhibitors as Potential Treatment and Diagnostic Target for Cancer
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Enzyme | Location | Function | Ref. | |
---|---|---|---|---|
Writers | METTL3 | nucleus and cytoplasm | a catalytic subunit of METTL3/METTL14 dipolymer | [28,45] |
METTL14 | nucleus | a platform for METTL3 in the process of RNA recognition and catalyzation | [13,45] | |
METTL16 | nucleus and cytoplasm | A catalytic subunit methylating U6 snRNA, MALAT1, and XIST | [21,46] | |
ZC3H13 | nucleus | bridges between RBM15/15B and WTAP and promotes the localization of MTC in the nucleus | [20] | |
VIRMA | nucleus | recruits METTL3/METTL14/WTAP to catalyze selective methylation on specific region of RNA | [18] | |
WTAP | nuclear speckle | mediates the localization of METTL3 and METTL14 into nuclear speckles | [47] | |
HAKAI | - | stabilizes the methyltransferase complex | [48] | |
RBM15/15B | - | mediates m6A formation in XIST | [36] | |
METTL5 | nucleolus and synapse | an enzyme mediating 18S rRNA m6A modification | [49,50] | |
TRMT112 | nucleus | a methyltransferase activator attaching to METTL5 to mediate m6A modification | [51,52,53] | |
ZCCHC4 | nucleolus | an enzyme mediating 28S rRNA m6A modification | [54,55] | |
Erasers | FTO | nucleus and cytoplasm | demethylates m6A unspecifically | [24,28] |
ALKBH5 | nucleus | demethylates m6A via oxidation | [24,28] | |
ALKBH3 | nucleus and cytoplasm | catalyzes m6A demethylation on tRNA | [27] | |
Reader | YTHDF1 | cytoplasm | YTHDF1, YTHDF2, and YTHDF3 act together to induce the degradation of mRNA | [56] |
YTHDF2 | cytoplasm | [56] | ||
YTHDF3 | cytoplasm | [56] | ||
YTHDC1 | nucleus | binds to noncoding RNAs like XIST to repress transcription | [57,58] | |
YTHDC2 | nucleus and cytoplasm | promotes RNA translation; predominately mediates the degradation of mRNA | [38,59,60] | |
HNRNPA2B1 | nucleus | promotes primary miRNA processing | [33,35] | |
HNRNPG | nucleus | regulates the expression and the splicing process of objective mRNAs | [41] | |
HNRNPC | nucleus | binds to flanking sequence of RNA to engage in precursor mRNAs (pre-mRNAs) splicing | [34] | |
IGF2BP1/2/3 | nucleus and cytoplasm | promotes the stability of mRNA under both normal and stress conditions | [42] | |
FMRP | nucleus and cytoplasm | stabilizes mRNA via m6A-modification | [61] |
Related ncRNA | Regulator Name | Function | Mechanism | Ref. |
---|---|---|---|---|
miRNA | METTL3 | 1. promotes oncogenesis | ① causes bladder cancer by accelerating maturation of pri-miR221/222 via interplaying with DGCR8 | [65] |
② causes pancreatic cancer by affecting maturation of miR-25-3p and subsequently prohibits PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) which provokes AKT-p70S6K | [67] | |||
2. facilitates resistance to 5-Fluorouracil (5-FU) | interacts with DGCR8 to modify miR-181d-5p | [66] | ||
METTL14 | suppresses oncogenesis | reduces hepatocelluar carcinoma by prohibiting the expression of miRNA 126 | [68] | |
FTO | promotes the expression of GTPase 5B (ARL5B) in breast cancer cells | Inhibits miR-181b-3p in the FTO/miR-181b-3p/ARL5B axis | [69] | |
ALKBH5 | suppresses oncogenesis | Reduces the expression of miR-107 in the oncogenesis of nonsmall-cell lung cancer (NSCLC) | [70,71] | |
RALY(HNRNPCL2) | promotes oncogenesis | causes colorectal cancer (CRC) by processing maturation of miR-483, miR-676, and miR-877 | [72] | |
HNRNPA2B1 | facilitates resistance to tamoxifen in breast cancer | reduces the expression of miRNA | [33] | |
lncRNA | METTL3 | promotes oncogenesis | ① promotes lymphatic metastasis by activating THAP7-AS1 | [77] |
② causes NSCLC by promoting the expression of ABHD11-AS1 | [78] | |||
METTL14 | suppresses oncogenesis | reduces CRC by facilitating m6A modification on Xist | [76] | |
METTL3/METTL14 | promotes oncogenesis | causes nasopharyngeal carcinoma (NPC) by stabilizing LNCAROD | [79] | |
WTAP | promotes oncogenesis | promotes growth and metastasis of NPC by stabilizing m6A methylation of DIAPH1-AS1 | [80] | |
FTO | promotes oncogenesis | causes the upregulation of LINC00022 in esophageal squamous cell carcinoma (ESCC) cells | [81,82,83] | |
IGF2BP1 | promotes oncogenesis | indirectly causes tumor by recognizing m6A on mRNA with the assistance of lncRNA-decoded protein | [85] | |
IGF2BP2 | promotes oncogenesis | causes pancreatic cancer by combing with LncRNA-PACERR | [84] | |
circRNA | METTL3 | promotes oncogenesis | causes NSCLC by impairing immune response of cancer via methylating circIGF2BP3 | [90] |
YTHDC1 | promotes oncogenesis | causes the transfer of circNSUN2 from nucleus to cytoplasm in liver-metastatic colon cancer | [91] | |
YTHDF2 | facilitates resistance to gefitinib | Induces endoribonucleolytic cleavage to downregulate m6A-modified circASK1 | [93] |
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Ma, M.; Ye, T.; Wang, J.; Zhao, H.; Zhang, S.; Li, P.; Zhao, G. N6-methyladenosine Modification of Noncoding RNAs: Mechanisms and Clinical Applications in Cancer. Diagnostics 2022, 12, 2996. https://doi.org/10.3390/diagnostics12122996
Ma M, Ye T, Wang J, Zhao H, Zhang S, Li P, Zhao G. N6-methyladenosine Modification of Noncoding RNAs: Mechanisms and Clinical Applications in Cancer. Diagnostics. 2022; 12(12):2996. https://doi.org/10.3390/diagnostics12122996
Chicago/Turabian StyleMa, Mingyang, Tong Ye, Jiewei Wang, Haiying Zhao, Shutian Zhang, Peng Li, and Guiping Zhao. 2022. "N6-methyladenosine Modification of Noncoding RNAs: Mechanisms and Clinical Applications in Cancer" Diagnostics 12, no. 12: 2996. https://doi.org/10.3390/diagnostics12122996