A-485 treatment potently downregulates SOX10 target genes in melanoma cells. A–C, IPC-298, CO79, and A375 cells were treated with 5 µmol/L A-485 for 24 hours, and RNA-seq was performed. Volcano plots of DEGs in each cell line are depicted (DEGs defined as FC > |2| and P < 0.05). D, The top five GO biological process pathways are shown for downregulated genes in each cell line. E, A heatmap of DEGs resulting from SOX10 KD in A375 cells is shown (data from GSE50535). F, The top five GO biological process pathways are shown for SOX10-activated genes (i.e., genes downregulated by SOX10 KD). G, A-485 downregulates GO biological process pathways that are activated by SOX10 in IPC-298, CO79, and A375 cells. H, Volcano plots of SOX10-activated genes differentially expressed due to A-485 treatment for IPC-298, CO79, and A375 cells. I–K, GO biological process pathways are shown for SOX10-activated genes that are downregulated by A-485.
ARTICLE ABSTRACT
SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth; on the other hand, SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in melanoma proliferation while preventing a concomitant increase in tumor cell invasion. In this study, we report that the lysine acetyltransferase (KAT) EP300 and SOX10 gene loci on chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor A-485 downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlow melanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.
The p300 KAT inhibitor A-485 blocks SOX10-dependent proliferation and SOX10-independent invasion in hard-to-treat melanoma cells.
