METTL3 regulates breast cancer-associated alternative splicing switches

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-6-methyladenosine (m(6)A), 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 m(6)A-methyltransferase in tumorigenesis. Specifically, we find that both m(6)A 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.

Automated summary

This study identifies a specific alternative splicing (AS) signature associated with breast tumorigenesis and reveals the role of METTL3 in modulating breast cancer-associated AS programs. It also demonstrates that m(6)A deposition in splice site boundaries and in splicing and transcription factor transcripts can directly regulate AS switches of specific breast cancer-associated transcripts. Furthermore, the study suggests that five validated AS events in vitro are associated with a poor overall survival rate for patients with breast cancer, indicating their potential as novel prognostic biomarkers.