# The CoREST Complex Regulates Alternative Splicing by the Transcriptional Regulation of RNA Processing Genes in Melanoma Cells

## TL;DR

The CoREST complex regulates RNA splicing in melanoma cells by controlling RNA processing genes, and its disruption affects cell viability and splicing patterns.

## Contribution

The paper identifies a novel CoREST-NOLC1 axis as a transcriptional regulatory mechanism in RNA splicing and melanoma treatment.

## Key findings

- Genetic or pharmacological inhibition of the CoREST complex disrupts spliceosome activity and reduces cell viability in melanoma cells.
- NOLC1, a downstream target of CoREST, partially rescues splicing defects and U1 snRNA methylation in CoREST-deficient cells.
- NOLC1 depletion increases sensitivity of melanoma cells to the MEK inhibitor trametinib.

## Abstract

RNA maturation, particularly splicing, depends on coordinated actions of RNA-binding proteins through post-transcriptional processing and constitutes a central mechanism of gene regulation. Aberrant splicing is associated with various diseases, including cancer. Here, we show that the CoREST complex, in coordination with c-MYC, transcriptionally regulates a subset of RNA processing genes, including those encoding essential small nuclear ribonucleoproteins (snRNPs) required for proper spliceosome function. Genetic depletion or the pharmacological inhibition of the CoREST complex in melanoma cells disrupted spliceosome activity, leading to widespread changes in alternative mRNA isoform expression and reduced cell viability. These splicing alterations were associated with changes in the 2′-O-methylation (Nm) of U1 snRNA, a modification critical for spliceosomal function. The ectopic expression of the nucleolar protein NOLC1, a downstream target of the CoREST complex and known for its role in ribosomal RNA processing, partially rescued viability, splicing patterns, and U1 snRNA methylation in CoREST-deficient melanoma cells. Conversely, NOLC1 depletion sensitized melanoma cells to the MEK inhibitor trametinib, a clinical drug approved for treating advanced melanoma. Together, these findings uncover a novel CoREST-NOLC1 axis which is a transcriptional regulatory mechanism playing a significant role in RNA splicing, highlighting that NOLC1 is a downstream effector of the CoREST complex and a potential therapeutic target for melanoma treatment.