Dynamic landscape of m6A modifications and related post-transcriptional events in muscle-invasive bladder cancer

作者：Lili Zhang, Ziwei Chen, Gaoyuan Sun, Chang Li, Pengjie Wu, Wenrui Xu, Hui Zhu, Zaifeng Zhang, Yongbin Tang, Yayu Li, Yifei Li, Siyuan Xu, Hexin Li, Meng Chen, Fei Xiao, Yaqun Zhang, Wei Zhang · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05701-x · 被引用次数：10 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Epigenetics and DNA Methylation

BACKGROUND: Muscle-invasive bladder carcinoma (MIBC) is a serious and more advanced stage of bladder carcinoma. N6-Methyladenosine (m6A) is a dynamic and reversible modifications that primarily affects RNA stability and alternative splicing. The dysregulation of m6A in MIBC can be potential target for clinical interventions, but there have been limited studies on m6A modifications in MIBC and their associations with post-transcriptional regulatory processes. METHODS: Paired tumor and adjacent-normal tissues were obtained from three patients with MIBC following radical cystectomy. The additional paired tissues for validation were obtained from patients underwent transurethral resection. Utilizing Nanopore direct-RNA sequencing, we characterized the m6A RNA methylation landscape in MIBC, with a focus on identifying post-transcriptional events potentially affected by changes in m6A sites. This included an examination of differential transcript usage, polyadenylation signal sites, and variations in poly(A) tail length, providing insights into the broader impact of m6A alterations on RNA processing in MIBC. RESULTS: The prognostic-related m6A genes and m6A-risk model constructed by machine learning enables the stratification of high and low-risk patients with precision. A novel m6A modification site in the 3' untranslated region (3'UTR) of IGLL5 gene were identified, characterized by a lower m6A methylation ratio, elongated poly(A) tails, and a notable bias in transcript usage. Fu...