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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2020-12, Vol.22 (12), p.702-713
• Main Authors: Chen, Yi-Su, Liu, Chao-Wei, Lin, Ying-Chin, Tsai, Chia-Ying, Yang, Ching-Hui, Lin, Jung-Chun
• Format: Article
• Language: English
• Subjects: Acin1; Alternative splicing; Colorectal cancer; MBNL; Original Research; SRSF3
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2020.10.002

•Differential splicing profiles of MBNL1 and Acin1 gene is noted in CRC tissues or cells.•Autoregulated exclusion of MBNL1 exons is altered with upregulated SRSF3•MBNL1 isoform differentially modulates CRC-related AS events.•SRSF3 and MBNL1 exerts opposite impact on expression of the Acin1 isoform.•Acin1 isoform exhibits distinct influence on DNA fragmentation in CRC cells.•SRSF3-MBNL11-Acin1 constitutes an emerging circuit involved in apoptosis of CRC cells. 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.