RNA m<sup>6</sup>A methyltransferase METTL3 promotes colorectal cancer cell proliferation and invasion by regulating Snail expression

Wen,Jianfan; Zhang,Guowei; Meng,Yuwen; Zhang,Lei; Jiang,Min; Yu,Zhitao

doi:10.3892/ol.2021.12972

October-2021 Volume 22 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

October-2021 Volume 22 Issue 4

Full Size Image

Article Open Access

RNA m⁶A methyltransferase METTL3 promotes colorectal cancer cell proliferation and invasion by regulating Snail expression

Authors:
- Jianfan Wen
- Guowei Zhang
- Yuwen Meng
- Lei Zhang
- Min Jiang
- Zhitao Yu
View Affiliations / Copyright

Affiliations: Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China

Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 711
|
Published online on: August 5, 2021

https://doi.org/10.3892/ol.2021.12972
Expand metrics +

Abstract

Nitrogen 6‑methyladenosine (m⁶A) is the result of methylation of nitrogen‑6 on adenosine, and is the most abundant chemical modification of eukaryotic mRNA. Dysregulation of m⁶A methylation has been implicated in cancer development and progression through various mechanisms. This type of methylation is primarily regulated by methyltransferase‑like 3 (METTL3). However, the molecular mechanisms underlying the role of METTL3 in colorectal cancer (CRC) have not been extensively elucidated. The present study explored m⁶A modification and the underlying mechanism of m⁶A, which serve regulatory roles in the development of CRC. It was found that METTL3 is upregulated in CRC cell lines and tissues, and its expression positively correlated with poor overall survival (OS). Mechanistically, the present study demonstrated that METTL3 methylates Snail mRNA, thus stabilizing it to promote CRC malignancy. The present findings indicate that m6A modification is involved in CRC tumorigenesis, and highlight its potential as a therapeutic target against CRC.

View Figures

View References

1	Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RG, Barzi A and Jemal A: Colorectal cancer statistics, 2017. CA Cancer J Clin. 67:177–193. 2017. View Article : Google Scholar : PubMed/NCBI
2	National Health Commission of The People's Republic of China, . National guidelines for diagnosis and treatment of colorectal cancer 2020 in China (English version). Chin J Cancer Res. 32:415–445. 2020. View Article : Google Scholar : PubMed/NCBI
3	Degiuli M, Reddavid R, Ricceri F, Di Candido F, Ortenzi M, Elmore U, Belluco C, Rosati R, Guerrieri M and Spinelli A; Members of the Italian Society of Surgical Oncology Colorectal Cancer Network (SICO-CCN) Collaborative Group, : Segmental colonic resection is a safe and effective treatment option for colon cancer of the splenic flexure: A nationwide retrospective study of the italian society of surgical oncology-colorectal cancer network collaborative group. Dis Colon Rectum. 63:1372–1382. 2020. View Article : Google Scholar : PubMed/NCBI
4	Tang R, Cheng AJ, Wang JY and Wang TC: Close correlation between telomerase expression and adenomatous polyp progression in multistep colorectal carcinogenesis. Cancer Res. 58:4052–4054. 1998.PubMed/NCBI
5	Pichler M, Stiegelbauer V, Vychytilova-Faltejskova P, Ivan C, Ling H, Winter E, Zhang X, Goblirsch M, Wulf-Goldenberg A, Ohtsuka M, et al: Genome-Wide miRNA analysis identifies miR-188-3p as a novel prognostic marker and molecular factor involved in colorectal carcinogenesis. Clin Cancer Res. 23:1323–1333. 2017. View Article : Google Scholar : PubMed/NCBI
6	Sun T, Wu R and Ming L: The role of m⁶A RNA methylation in cancer. Biomed Pharmacother. 112:1086132019. View Article : Google Scholar : PubMed/NCBI
7	Zhang C, Chen Y, Sun B, Wang L, Yang Y, Ma D, Lv J, Heng J, Ding Y, Xue Y, et al: m⁶A modulates haematopoietic stem and progenitor cell specification. Nature. 549:273–276. 2017. View Article : Google Scholar : PubMed/NCBI
8	Di Timoteo G, Dattilo D, Centron-Broco A, Colantoni A, Guarnacci M, Rossi F, Incarnato D, Oliviero S, Fatica A, Morlando M and Bozzoni I: Modulation of circRNA metabolism by m⁶A modification. Cell Rep. 31:1076412020. View Article : Google Scholar : PubMed/NCBI
9	Chen F, Chen Z, Guan T, Zhou Y, Ge L, Zhang H, Wu Y, Jiang GM, He W, Li J and Wang H: N⁶-Methyladenosine regulates mRNA stability and translation efficiency of KRT7 to promote breast cancer lung metastasis. Cancer Res. 81:2847–2860. 2021. View Article : Google Scholar : PubMed/NCBI
10	Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR: Comprehensive analysis of mRNA methylation reveals enrichment in 3′UTRs and near stop codons. Cell. 149:1635–1646. 2012. View Article : Google Scholar : PubMed/NCBI
11	Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, Li J, An P, Lu L, Luo N, et al: m⁶A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 18:872019. View Article : Google Scholar : PubMed/NCBI
12	Alarcon CR, Lee H, Goodarzi H, Halberg N and Tavazoie SF: N⁶-methyladenosine marks primary microRNAs for processing. Nature. 519:482–485. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, et al: N⁶-methyladenosine-dependent regulation of messenger RNA stability. Nature. 505:117–120. 2014. View Article : Google Scholar : PubMed/NCBI
14	Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H and He C: N⁶-methyladenosine modulates messenger RNA translation efficiency. Cell. 161:1388–1399. 2015. View Article : Google Scholar : PubMed/NCBI
15	Jia G, Fu Y and He C: Reversible RNA adenosine methylation in biological regulation. Trends Genet. 29:108–115. 2013. View Article : Google Scholar : PubMed/NCBI
16	Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, et al: Perturbation of m⁶A writers reveals two distinct classes of mRNA methylation at internal and 5′sites. Cell Rep. 8:284–296. 2014. View Article : Google Scholar : PubMed/NCBI
17	Zhou T, Ren Z and Chen C: METTL14 as a predictor of postoperative survival outcomes of patients with hepatocellular carcinoma. Nan Fang Yi Ke Da Xue Xue Bao. 40:567–572. 2020.(In Chinese). PubMed/NCBI
18	Mathiyalagan P, Adamiak M, Mayourian J, Sassi Y, Liang Y, Agarwal N, Jha D, Zhang S, Kohlbrenner E, Chepurko E, et al: FTO-Dependent N⁶-methyladenosine regulates cardiac function during remodeling and repair. Circulation. 139:518–532. 2019. View Article : Google Scholar : PubMed/NCBI
19	Xu K, Mo Y, Li D, Yu Q, Wang L, Lin F, Kong C, Balelang MF, Zhang A, Chen S, et al: N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury. Ther Adv Chronic Dis. 11:20406223209160242020. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Cheng X, Wang J, Huang Y, Yuan J and Guo D: Gene signature and prognostic merit of M6a regulators in colorectal cancer. Exp Biol Med (Maywood). 245:1344–1354. 2020. View Article : Google Scholar : PubMed/NCBI
21	Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, Chen ZH, Zeng ZL, Wang F, Zheng J, et al: METTL3 facilitates tumor progression via an m⁶A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 18:1122019. View Article : Google Scholar : PubMed/NCBI
22	Yang DD, Chen ZH, Yu K, Lu JH, Wu QN, Wang Y, Ju HQ, Xu RH, Liu ZX and Zeng ZL: METTL3 Promotes the progression of gastric cancer via targeting the MYC Pathway. Front Oncol. 10:1152020. View Article : Google Scholar : PubMed/NCBI
23	Zhou D, Tang W, Xu Y, Xu Y, Xu B, Fu S, Wang Y, Chen F, Chen Y, Han Y and Wang G: METTL3/YTHDF2 m⁶A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5. Mol Oncol. Jan 7–2021.doi: 10.1002/1878-0261.12898 (Epub ahead of print). View Article : Google Scholar
24	Zhu W, Si Y, Xu J, Lin Y, Wang JZ, Cao M, Sun S, Ding Q, Zhu L and Wei JF: Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m⁶A-dependent manner. J Cell Mol Med. 24:3521–3533. 2020. View Article : Google Scholar : PubMed/NCBI
25	Deng R, Cheng Y, Ye S, Zhang J, Huang R, Li P, Liu H, Deng Q, Wu X, Lan P and Deng Y: m⁶A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ERK pathways. Onco Targets Ther. 12:4391–4402. 2019. View Article : Google Scholar : PubMed/NCBI
26	Yu X, Zhao H and Cao Z: The m⁶A methyltransferase METTL3 aggravates the progression of nasopharyngeal carcinoma through inducing EMT by m⁶A-modified Snail mRNA. Minerva Med. Jun 5–2020.doi: 10.23736/S0026-4806.20.06653-7 (Epub ahead of print).
27	Lin X, Chai G, Wu Y, Li J, Chen F, Liu J, Luo G, Tauler J, Du J, Lin S, et al: RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 10:20652019. View Article : Google Scholar : PubMed/NCBI
28	Wang Y, Wu Z and Hu L: The regulatory effects of metformin on the [SNAIL/miR-34]:[ZEB/miR-200] system in the epithelial-mesenchymal transition(EMT) for colorectal cancer(CRC). Eur J Pharmacol. 834:45–53. 2018. View Article : Google Scholar : PubMed/NCBI
29	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
30	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
31	Ahadi M, Sokolova A, Brown I, Chou A and Gill AJ: The 2019 World Health Organization Classification of appendiceal, colorectal and anal canal tumours: An update and critical assessment. Pathology. 53:454–461. 2021. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
33	Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al: Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq. Nature. 485:201–206. 2012. View Article : Google Scholar : PubMed/NCBI
34	Hentze MW: Determinants and regulation of cytoplasmic mRNA stability in eukaryotic cells. Biochim Biophys Acta. 1090:281–292. 1991. View Article : Google Scholar : PubMed/NCBI
35	Yang G, Sun Z and Zhang N: Reshaping the role of m⁶A modification in cancer transcriptome: A review. Cancer Cell Int. 20:3532020. View Article : Google Scholar : PubMed/NCBI
36	Wu L, Wu D, Ning J, Liu W and Zhang D: Changes of N⁶-methyladenosine modulators promote breast cancer progression. BMC Cancer. 19:3262019. View Article : Google Scholar : PubMed/NCBI
37	Wang H, Zhao X and Lu Z: m⁶A RNA methylation regulators act as potential prognostic biomarkers in lung adenocarcinoma. Front Genet. 12:6222332021. View Article : Google Scholar : PubMed/NCBI
38	Tian J, Ying P, Ke J, Zhu Y, Yang Y, Gong Y, Zou D, Peng X, Yang N, Wang X, et al: ANKLE1 N⁶-Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. Int J Cancer. 146:3281–3293. 2020. View Article : Google Scholar : PubMed/NCBI
39	Huo FC, Zhu ZM, Zhu WT, Du QY, Liang J and Mou J: METTL3-mediated m⁶A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2. Oncogene. 40:2968–2981. 2021. View Article : Google Scholar : PubMed/NCBI
40	Lan H, Liu Y, Liu J, Wang X, Guan Z, Du J and Jin K: Tumor-associated macrophages promote oxaliplatin resistance via METTL3-mediated m⁶A of TRAF5 and necroptosis in colorectal cancer. Mol Pharm. 18:1026–1037. 2021. View Article : Google Scholar : PubMed/NCBI
41	Chen H, Gao S, Liu W, Wong CC, Wu J, Wu J, Liu D, Gou H, Kang W, Zhai J, et al: RNA N⁶-Methyladenosine methyltransferase METTL3 facilitates colorectal cancer by activating the m⁶A-GLUT1-mTORC1 axis and is a therapeutic target. Gastroenterology. 160:1284–1300.e16. 2021. View Article : Google Scholar : PubMed/NCBI
42	Peng W, Li J, Chen R, Gu Q, Yang P, Qian W, Ji D, Wang Q, Zhang Z, Tang J and Sun Y: Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway. J Exp Clin Cancer Res. 38:3932019. View Article : Google Scholar : PubMed/NCBI
43	Shen C, Xuan B, Yan T, Ma Y, Xu P, Tian X, Zhang X, Cao Y, Ma D, Zhu X, et al: m⁶A-dependent glycolysis enhances colorectal cancer progression. Mol Cancer. 19:722020. View Article : Google Scholar : PubMed/NCBI
44	Yang Y, Hsu PJ, Chen YS and Yang YG: Dynamic transcriptomic m⁶A decoration: Writers, erasers, readers and functions in RNA metabolism. Cell Res. 28:616–624. 2018. View Article : Google Scholar : PubMed/NCBI
45	Zhen D, Wu Y, Zhang Y, Chen K, Song B, Xu H, Tang Y, Wei Z and Meng J: m⁶A Reader: Epitranscriptome target prediction and functional characterization of N⁶-methyladenosine (m⁶A) readers. Front Cell Dev Biol. 8:7412020. View Article : Google Scholar : PubMed/NCBI
46	Kudo-Saito C, Shirako H, Takeuchi T and Kawakami Y: Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 15:195–206. 2009. View Article : Google Scholar : PubMed/NCBI
47	Dominguez D, Montserrat-Sentís B, Virgós-Soler A, Guaita S, Grueso J, Porta M, Puig I, Baulida J, Francí C and García de Herreros A: Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol Cell Biol. 23:5078–5089. 2003. View Article : Google Scholar : PubMed/NCBI

Journals