Ryu, B.; Khan, A. A.; Aptekmann, A. A.; Byun, J.; Min, D.; Povelaitis, M. C.; Shin, J.; Zakrzewski, J. L.

The maturation of RNA is mediated by the coordinated actions of RNA-binding proteins through post-transcriptional pre-mRNA processing. This process is a central regulatory mechanism for gene expression and plays a crucial role in the development of complex biological systems. MYC directly upregulates transcription of genes encoding the core components of pre-mRNA splicing machinery. The perturbation of splicing processes is associated with various disease conditions, including cancer. Here, we report that the CoREST complex stabilizes MYC from proteolytic degradation via post-translational modification through site-specific deacetylation of lysine residues. Furthermore, the CoREST complex acts as a transcriptional coregulator of MYC-driven transcriptional activation of RNA processing genes. These genes include those encoding snRNPs and snoRNPs that are important players in pre-mRNA spliceosome fidelity. Genetic ablation and pharmacological inhibition of the CoREST complex in melanoma cells induce altered spliceosome activity. These alterations result in significant changes in genome-wide expression patterns of alternatively spliced mRNA isoforms and compromise cell survival. The ectopic expression of one of the RNA processing genes, NOLC1, partially restores cell viability in the CoREST complex-depleted cells. These findings identify the interaction of the CoREST-complex with MYC as a central regulator of cancer-specific expression profiles of mRNA splicing variants.