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METTL3/YTHDF2 mA 轴通过降解膀胱癌中的 SETD7 和 KLF4 mRNA 促进肿瘤发生。

METTL3/YTHDF2 m A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer.

机构信息

Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.

出版信息

J Cell Mol Med. 2020 Apr;24(7):4092-4104. doi: 10.1111/jcmm.15063. Epub 2020 Mar 3.

DOI:10.1111/jcmm.15063
PMID:32126149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7171394/
Abstract

N6-Methyladenosine (m A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.

摘要

N6-甲基腺苷（m6A）修饰是真核信使 RNA（mRNA）中最普遍的修饰，参与多种肿瘤的进展。然而，m6A 在膀胱癌（BCa）中的具体作用仍知之甚少。在这项研究中，我们证明了由核心“书写器”蛋白 METTL3 和主要读码蛋白 YTHDF2 组成的 m6A 轴具有促进肿瘤的功能和特定的调节机制。METTL3 的耗竭会损害体外和体内的癌症增殖和癌症转移。通过转录组测序、m6A 甲基化 RNA 免疫沉淀（MeRIP）和 RIP，我们确定了 METTL3/YTHDF2 m6A 轴直接降解肿瘤抑制因子 SETD7 和 KLF4 的 mRNA，促进了 BCa 的进展。此外，SETD7 和 KLF4 的过表达显示出与 m6A 轴耗竭诱导的表型一致。因此，我们关于 METTL3/YTHDF2/SETD7/KLF4 m6A 轴的发现提供了对致癌发生潜在机制的深入了解，并强调了 BCa 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/5e29077dbbe8/JCMM-24-4092-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/d768478eb361/JCMM-24-4092-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/88c5cc8aa349/JCMM-24-4092-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/5985cb73f8b4/JCMM-24-4092-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/d4af54ff101b/JCMM-24-4092-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/baafd20d6340/JCMM-24-4092-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/89c008691392/JCMM-24-4092-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/5e29077dbbe8/JCMM-24-4092-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/d768478eb361/JCMM-24-4092-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/88c5cc8aa349/JCMM-24-4092-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/5985cb73f8b4/JCMM-24-4092-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/d4af54ff101b/JCMM-24-4092-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/baafd20d6340/JCMM-24-4092-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/89c008691392/JCMM-24-4092-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e94/7171394/5e29077dbbe8/JCMM-24-4092-g007.jpg

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