259 The CoREST complex modulates phenotype plasticity in human melanoma

The epithelial-to-mesenchymal transition (EMT) is an essential and reversible embryonic phenomenon that produces motile cells from polarized epithelia via epigenetic reprogramming, allows for a switch between invasive, proliferative, drug-resistant phenotypes in carcinomas, associated with higher risk of metastasis worse prognosis. This has been observed non-epithelial cancers, as well, including melanoma. Several transcriptional factors (ZEB, SNAIL, TWIST, etc.) have shown to govern phenotype plasticity epithelial cancers; however, their precise mechanism context-dependent. We found the CoREST complex, epigenetic-modifying complex histone deacetylase (HDAC) lysine-specific demethylase 1 (LSD1) activity, plays critical role switching Here, we demonstrate inhibition corin, novel dual HDAC1/2 LSD1 inhibitor, reduces melanoma invasion focal adhesion puncta 1205Lu cells. Using RNAseq, observe KEGG cell molecules pathway be enriched upregulated treated corin find genes invasive (AXL, WNT5A, TGFBR1, TEAD2, ZEB1) significantly downregulated following treatment, while those proliferative (MITF, SOX10, PAX3, MLANA) are supporting corin's ability induce Investigation effects ChIPseq demonstrates decreased H3K27ac H3K9ac occupancy at AXL, ZEB1 TWIST1/2 promoters, corin’s alter transcription plasticity-related reprogramming. data suggests mediates malignant reprogramming EMT-associated downstream targets targeting this may clinical benefit cancers driven by EMT.