Alternative Splicing of MEF2C Controls its Activity in Normal Myogenesis and Promotes Tumorigenicity in Rhabdomyosarcoma Cells [Molecular Bases of Disease]

November 17th, 2014 by Zhang, M., Zhu, B., Davie, J.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Many cellular disruptions contribute to the progression of this pediatric cancer including aberrant alternative splicing. The MEF2 family of transcription factors regulates many developmental programs, including myogenesis. MEF2 gene transcripts are subject to alternate splicing to generate protein isoforms with divergent functions. We found that MEF2Cα1 was the ubiquitously expressed isoform which exhibited no myogenic activity and that MEF2Cα2, the muscle specific MEF2C isoform, was required for efficient differentiation. We showed that exon α in MEF2C was aberrantly alternatively spliced in RMS cells, with the ratio of α2/α1 highly downregulated in RMS cells compared with normal myoblasts. Compared with MEF2Cα2, MEF2Cα1 more strongly interacted with and recruited HDAC5 to myogenic gene promoters to repress muscle specific genes. Overexpression of the MEF2Cα2 isoform in RMS cells increased myogenic activity and promoted differentiation in RMS cells. We have also identified a serine protein kinase, SRPK3, which was downregulated in RMS cells and found that expression of SRPK3 promoted the splicing of the MEF2Cα2 isoform and induced differentiation. Restoration of either MEF2Cα2 or SPRK3 inhibited both proliferation and anchorage independent growth of RMS cells. Together, our findings indicate the alternative splicing of MEF2C plays an important role in normal myogenesis and RMS development. Improved understanding of alternative splicing events in RMS cells will potentially reveal novel therapeutic targets for RMS treatment.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Alternative Splicing of MEF2C Controls its Activity in Normal Myogenesis and Promotes Tumorigenicity in Rhabdomyosarcoma Cells [Molecular Bases of Disease]