Dissecting the effects of METTL3 on alternative splicing in prostate cancer

Frontiers in Oncology

Oncology

Lin Wang¹  Chi-Fai Ng²  Peter Ka-Fung Chiu²  Yiwei Wang³  Judy Kin-Wing Ng³  Cathy Sin-Hang Fung³  Jinpao Hou³  Ling Shi³  Lingyi Wang³  Yonghao Liang³  Chan Hoi Yin³  Stephen Kwok-Wing Tsui⁴ 

[1] Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China;SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China;Hong Kong Bioinformatics Centre, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China;

关键词: METTL3;    prostate cancer;    RNA splicing;    N 6 -methyladenosine;    MKNK2;    nanopore direct RNA sequencing;   

DOI  :  10.3389/fonc.2023.1227016

 received in 2023-05-22, accepted in 2023-07-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker.

【 授权许可】

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Copyright © 2023 Wang, Shi, Liang, Ng, Yin, Wang, Hou, Wang, Fung, Chiu, Ng and Tsui