Department of Molecular Biology, Umeå University, SE-901 87, Umeå, Sweden.
Wallenberg Centre for Molecular Medicine, Umeå University, SE-901 87, Umeå, Sweden.
Oncogene. 2023 Mar;42(12):911-925. doi: 10.1038/s41388-023-02602-z. Epub 2023 Feb 1.
Alternative splicing (AS) enables differential inclusion of exons from a given transcript, thereby contributing to the transcriptome and proteome diversity. Aberrant AS patterns play major roles in the development of different pathologies, including breast cancer. N-methyladenosine (mA), the most abundant internal modification of eukaryotic mRNA, influences tumor progression and metastasis of breast cancer, and it has been recently linked to AS regulation. Here, we identify a specific AS signature associated with breast tumorigenesis in vitro. We characterize for the first time the role of METTL3 in modulating breast cancer-associated AS programs, expanding the role of the mA-methyltransferase in tumorigenesis. Specifically, we find that both mA deposition in splice site boundaries and in splicing and transcription factor transcripts, such as MYC, direct AS switches of specific breast cancer-associated transcripts. Finally, we show that five of the AS events validated in vitro are associated with a poor overall survival rate for patients with breast cancer, suggesting the use of these AS events as a novel potential prognostic biomarker.
选择性剪接 (AS) 使给定转录本中的外显子差异包含成为可能，从而为转录组和蛋白质组多样性做出贡献。异常的 AS 模式在包括乳腺癌在内的不同病理的发展中起主要作用。N6-甲基腺苷 (m6A)，真核 mRNA 中最丰富的内部修饰，影响乳腺癌的肿瘤进展和转移，并且最近与 AS 调节有关。在这里，我们在体外鉴定出与乳腺癌发生相关的特定 AS 特征。我们首次描述了 METTL3 在调节乳腺癌相关 AS 程序中的作用，扩展了 mA-甲基转移酶在肿瘤发生中的作用。具体来说，我们发现剪接位点边界和剪接及转录因子转录本（如 MYC）中的 mA 沉积都可以指导特定的乳腺癌相关转录本的 AS 开关。最后，我们证明了在体外验证的五个 AS 事件与乳腺癌患者的整体生存率较差相关，这表明可以将这些 AS 事件用作新的潜在预后生物标志物。
