Ribosome 18S m<sup>6</sup>A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c‑Myc translation

Huang,Hua; Li,Huan; Pan,Ruining; Wang,Sijia; Khan,Aamir Ali; Zhao,Yue; Zhu,Huiyu; Liu,Xinhui

doi:10.3892/ijo.2021.5299

Ribosome 18S m⁶A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c‑Myc translation

Authors:
- Hua Huang
- Huan Li
- Ruining Pan
- Sijia Wang
- Aamir Ali Khan
- Yue Zhao
- Huiyu Zhu
- Xinhui Liu
View Affiliations

Affiliations: Center of Excellence for Environmental Safety and Biological Effects, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, P.R. China, Intensive Care Unit, Beijing Tsinghua Changgung Hospital, Beijing 102218, P.R. China, School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China
Published online on: December 28, 2021 https://doi.org/10.3892/ijo.2021.5299
Article Number: 9

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Methyltransferase N6‑adenosine (METTL5) is a methyltransferase that specifically catalyzes 18S rRNA N6 methylation at adenosine 1832 (m⁶A₁₈₃₂), which is located in a critical position in the decoding center, therefore suggesting its potential importance in the regulation of translation. However, the underlying mechanism of METTL5‑mediated translation regulation of specific genes and its biological functions are largely undefined. To the best of our knowledge, the present study demonstrated for the first time that METTL5 was an oncogene that promoted cell proliferation, migration, invasion and tumorigenesis in pancreatic cancer. In addition, the oncogenic function of METTL5 may involve an increase in c‑Myc translation, as evidenced by the fact that the oncogenic effect caused by METTL5 overexpression could be abolished by c‑Myc knockdown. Notably, m⁶A modifications at the 5' untranslated region (5'UTR) and coding DNA sequence region (near the 5'UTR) of c‑Myc mRNA played a critical role in the specific translation regulation by METTL5. In addition, it was further demonstrated that METTL5 and its cofactor tRNA methyltransferase activator subunit 11‑2 synergistically promote pancreatic cancer progression. These findings revealed important roles for METTL5 in the development of pancreatic cancer and present the METTL5/c‑Myc axis as a novel therapeutic strategy for treatment.

View Figures

View References

1	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
2	Bartosovic M, Molares HC, Gregorova P, Hrossova D, Kudla G and Vanacova S: N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing. Nucleic Acids Res. 45:11356–11370. 2017. View Article : Google Scholar : PubMed/NCBI
3	Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB and Jaffrey SR: 5′ UTR m(6)A promotes cap-independent translation. Cell. 163:999–1010. 2015. View Article : Google Scholar : PubMed/NCBI
4	Liu N, Dai Q, Zheng G, He C, Parisien M and Pan T: N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 518:560–564. 2015. View Article : Google Scholar : PubMed/NCBI
5	Roundtree IA, Evans ME, Pan T and He C: Dynamic RNA modifications in gene expression regulation. Cell. 169:1187–1200. 2017. View Article : Google Scholar : PubMed/NCBI
6	Natchiar SK, Myasnikov AG, Kratzat H, Hazemann I and Klaholz BP: Visualization of chemical modifications in the human 80S ribosome structure. Nature. 551:472–477. 2017. View Article : Google Scholar : PubMed/NCBI
7	Sergiev PV, Aleksashin NA, Chugunova AA, Polikanov YS and Dontsova OA: Structural and evolutionary insights into ribosomal RNA methylation. Nat Chem Biol. 14:226–235. 2018. View Article : Google Scholar : PubMed/NCBI
8	Ma H, Wang X, Cai J, Dai Q, Natchiar SK, Lv R, Chen K, Lu Z, Chen H, Shi YG, et al: N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat Chem Biol. 15:88–94. 2019. View Article : Google Scholar : PubMed/NCBI
9	Pinto R, Vagbo CB, Jakobsson ME, Kim Y, Baltissen MP, O'Donohue MF, Guzmán UH, Małecki JM, Wu J, Kirpekar F, et al: The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 48:830–846. 2020. View Article : Google Scholar : PubMed/NCBI
10	van Tran N, Ernst FGM, Hawley BR, Zorbas C, Ulryck N, Hackert P, Bohnsack KE, Bohnsack MT, Jaffrey SR, Graille M and Lafontaine DLJ: The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 47:7719–7733. 2019. View Article : Google Scholar : PubMed/NCBI
11	Rong B, Zhang Q, Wan J, Xing S, Dai R, Li Y, Cai J, Xie J, Song Y, Chen J, et al: Ribosome 18S m(6)A methyltransferase METTL5 promotes translation initiation and breast cancer cell growth. Cell Rep. 33:1085442020. View Article : Google Scholar : PubMed/NCBI
12	Ignatova VV, Stolz P, Kaiser S, Gustafsson TH, Lastres PR, Sanz-Moreno A, Cho YL, Amarie OV, Aguilar-Pimentel A, Klein-Rodewald T, et al: The rRNA m(6)A methyltransferase METTL5 is involved in pluripotency and developmental programs. Genes Dev. 34:715–729. 2020. View Article : Google Scholar : PubMed/NCBI
13	Wang L, Liang Y, Lin R, Xiong Q, Yu P, Ma J, Cheng M, Han H, Wang X, Wang G, et al: Mettl5 mediated 18S rRNA N6-methyladenosine (m6A) modification controls stem cell fate determination and neural function. Genes & Diseases. 9:268–274. 2022. View Article : Google Scholar
14	Xing M, Liu Q, Mao C, Zeng H, Zhang X, Zhao S, Chen L, Liu M, Shen B, Guo X, et al: The 18S rRNA m(6) A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation. EMBO Rep. 21:e498632020. View Article : Google Scholar : PubMed/NCBI
15	Leismann J, Spagnuolo M, Pradhan M, Wacheul L, Vu MA, Musheev M, Mier P, Andrade-Navarro MA, Graille M, Niehrs C, et al: The 18S ribosomal RNA m(6) A methyltransferase Mettl5 is required for normal walking behavior in Drosophila. EMBO Rep. 21:e494432020. View Article : Google Scholar : PubMed/NCBI
16	Yoshida GJ: Emerging roles of Myc in stem cell biology and novel tumor therapies. J Exp Clin Cancer Res. 37:1732018. View Article : Google Scholar : PubMed/NCBI
17	AlSultan D, Kavanagh E, O'Grady S, Eustace AJ, Castell A, Larsson LG, Crown J, Madden SF and Duffy MJ: The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells. Invest New Drugs. 39:587–594. 2021. View Article : Google Scholar : PubMed/NCBI
18	Destefanis F, Manara V and Bellosta P: Myc as a regulator of ribosome biogenesis and cell competition: A link to cancer. Int J Mol Sci. 21:40372020. View Article : Google Scholar : PubMed/NCBI
19	Wu H, Li F and Zhu R: miR-338-5p inhibits cell growth and migration via inhibition of the METTL3/m6A/c-Myc pathway in lung cancer. Acta Biochim Biophys Sin (Shanghai). 53:304–316. 2021. View Article : Google Scholar : PubMed/NCBI
20	Dang CV: MYC on the path to cancer. Cell. 149:22–35. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shan H, Cao Y, Xiao X, Liu M and Wu Y, Zhu Q, Xu H, Lei H, Yao Z and Wu Y: YL064 activates proteasomal-dependent degradation of c-Myc and synergistically enhances the anti-tumor activity of ABT-199 in diffuse large B cell lymphoma. Signal Transduct Target Ther. 5:1162020. View Article : Google Scholar : PubMed/NCBI
22	Yang G, Xiong G, Feng M, Zhao F, Qiu J, Liu Y, Cao Z, Wang H, Yang J, You L, et al: OLR1 promotes pancreatic cancer metastasis via increased c-Myc expression and transcription of HMGA2. Mol Cancer Res. 18:685–697. 2020. View Article : Google Scholar : PubMed/NCBI
23	Zhong Y, Yang L, Xiong F, He Y, Tang Y, Shi L, Fan S, Li Z, Zhang S, Gong Z, et al: Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc. Signal Transduct Target Ther. 6:2402021. View Article : Google Scholar : PubMed/NCBI
24	Shams R, Aghdaei HA, Behmanesh A, Sadeghi A, Zali M, Salari S and Padrón JM: MicroRNAs targeting MYC expression: Trace of hope for pancreatic cancer therapy. A systematic review. Cancer Manag Res. 12:2393–2404. 2020. View Article : Google Scholar : PubMed/NCBI
25	Hessmann E, Schneider G, Ellenrieder V and Siveke JT: MYC in pancreatic cancer: Novel mechanistic insights and their translation into therapeutic strategies. Oncogene. 35:1609–1618. 2016. View Article : Google Scholar : PubMed/NCBI
26	Wang XS, He JR, Yu S and Yu J: Methyltransferase-like 3 promotes the proliferation of acute myeloid leukemia cells by regulating N6-methyladenosine Levels of MYC. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 40:308–314. 2018.(In Chinese). PubMed/NCBI
27	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
28	Chen H, Liu Q, Yu D, Natchiar K, Zhou C, Hsu CH, Hsu PH, Zhang X, Klaholz B, Gregory RI, et al: METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes. bioRxiv. doi: 10.1101/2020.04.27.064162.
29	Lin S, Choe J, Du P, Triboulet R and Gregory RI: The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 62:335–345. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wilson C, Chen PJ, Miao Z and Liu DR: Programmable m(6)A modification of cellular RNAs with a Cas13-directed methyltransferase. Nat Biotechnol. 38:1431–1440. 2020. View Article : Google Scholar : PubMed/NCBI
31	Konermann S, Lotfy P, Brideau NJ, Oki J, Shokhirev MN and Hsu PD: Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell. 173:665–676, e614. 2018. View Article : Google Scholar : PubMed/NCBI
32	Li S, Li X, Xue W, Zhang L, Yang LZ, Cao SM, Lei YN, Liu CX, Guo SK, Shan L, et al: Screening for functional circular RNAs using the CRISPR-Cas13 system. Nat Methods. 18:51–59. 2021. View Article : Google Scholar : PubMed/NCBI
33	Liger D, Mora L, Lazar N, Figaro S, Henri J, Scrima N, Buckingham RH, van Tilbeurgh H, Heurgué-Hamard V and Graille M: Mechanism of activation of methyltransferases involved in translation by the Trm112 ‘hub’ protein. Nucleic Acids Res. 44:14822016. View Article : Google Scholar : PubMed/NCBI