The SRSF3-MBNL1-Acin1 circuit constitutes an emerging axis to lessen DNA fragmentation in colorectal cancer via an alternative splicing mechanism

• Main Authors: Yi-Su Chen, Chao-Wei Liu, Ying-Chin Lin, Chia-Ying Tsai, Ching-Hui Yang, Jung-Chun Lin
• Format: Article
• Language: English
• Published: Elsevier 2020-12-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: Acin1; Alternative splicing; Colorectal cancer; MBNL; SRSF3
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558620301573

ABSTRACT: Altered alternative splicing (AS) events are considered pervasive causes that result in the development of carcinogenesis. Herein, we identified reprogrammed expression and splicing profiles of Muscle blind-like protein 1 (MBNL1) transcripts in tumorous tissues compared to those of adjacent normal tissues dissected from individual colorectal cancer (CRC) patients using whole-transcriptome analyses. MBNL1 transcript 8 (MBNL18) containing exons 5 and 7 was majorly generated by cancerous tissues and CRC-derived cell lines compared with those of the normal counterparts. Interplay between the exonic CA-rich element and upregulated SRSF3 facilitated the inclusion of MBNL1 exons 5 and 7, which encode a bipartite nuclear localization signal (NLS) and conformational NLS. Moreover, abundant SRSF3 interfered with the autoregulatory mechanism involved in utilization of MBNL1 exons 5 and 7, resulting in enrichment of the MBNL18 isoform in cultured CRC cell lines. Subsequently, an increase in the MBNL18 isoform drove a shift in the apoptotic chromatin condensation inducer in nucleus 1-S (Acin1-S) isoform to the Acin1-L isoform, leading to diminished DNA fragmentation in cultured CRC cells under oxidative stress. Taken together, SRSF3-MBNL1-Acin1 was demonstrated to constitute an emerging axis which is relevant to proapoptotic signatures and post-transcriptional events of CRC cells.