N6-methyladenosine-induced METTL1 promotes tumor proliferation via CDK4
Author:
Zhang Chunyan1, Cui Yuanbo2ORCID
Affiliation:
1. Department of Clinical Laboratory , Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou 450007 , China 2. Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou 450007 , China
Abstract
Abstract
N6-methyladenosine (m6A) and N7-methylguanosine (m7G) modification of RNA represent two major intracellular post-transcriptional regulation modes of gene expression. However, the crosstalk of these two epigenetic modifications in tumorigenesis remain poorly understood. Here, we show that m6A methyltransferase METTL3-mediated METTL1 promotes cell proliferation of head and neck squamous cell carcinoma (HNSC) through m7G modification of the cell-cycle regulator CDK4. By mining the database GEPIA, METTL1 was shown to be up-regulated in a broad spectrum of human cancers and correlated with patient clinical outcomes, particularly in HNSC. Mechanistically, METTL3 methylates METTL1 mRNA and mediates its elevation in HNSC via m6A. Functionally, over-expression of METTL1 enhances HNSC cell growth and facilitates cell-cycle progress, while METTL1 knockdown represses these biological behaviors. Moreover, METTL1 physically binds to CDK4 transcript and regulates its m7G modification level to stabilize CDK4. Importantly, the inhibitory effects of METTL1 knockdown on the proliferation of HNSC, esophageal cancer (ESCA), stomach adenocarcinoma (STAD), and colon adenocarcinoma (COAD) were significantly mitigated by over-expression of CDK4. Taken together, this study expands the understanding of epigenetic mechanisms involved in tumorigenesis and identifies the METTL1/CDK4 axis as a potential therapeutic target for digestive system tumors.
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
Reference35 articles.
1. An, Y. and Duan, H. (2022). The role of m6A RNA methylation in cancer metabolism. Mol. Cancer 21: 14, https://doi.org/10.1186/s12943-022-01500-4. 2. Barbieri, I. and Kouzarides, T. (2020). Role of RNA modifications in cancer. Nat. Rev. Cancer 20: 303–322, https://doi.org/10.1038/s41568-020-0253-2. 3. Boccaletto, P., Machnicka, M.A., Purta, E., Piatkowski, P., Baginski, B., Wirecki, T.K., de Crécy-Lagard, V., Ross, R., Limbach, P.A., Kotter, A., et al.. (2018). MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46: D303–D307, https://doi.org/10.1093/nar/gkx1030. 4. Chandrashekar, D.S., Karthikeyan, S.K., Korla, P.K., Patel, H., Shovon, A.R., Athar, M., Netto, G.J., Qin, Z.S., Kumar, S., Manne, U., et al.. (2022). UALCAN: an update to the integrated cancer data analysis platform. Neoplasia 25: 18–27, https://doi.org/10.1016/j.neo.2022.01.001. 5. Chaudhary, S., Pothuraju, R., Rachagani, S., Siddiqui, J.A., Atri, P., Mallya, K., Nasser, M.W., Sayed, Z., Lyden, E.R., Smith, L., et al.. (2021). Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring. Cancer Lett. 510: 79–92, https://doi.org/10.1016/j.canlet.2021.04.004.
|
|