A-485 induces proteasomal degradation of SOX10. A, A panel of melanoma cell lines were treated with DMSO (D) or 5 µmol/L A-485 (A) for 24 hours. SOX10 expression was assessed via RT-qPCR. B–D, IPC-298, CO79, and A375 cells were treated with 50 µg/mL CHX and/or 5 µmol/L MG-132 for the indicated time. SOX10 protein levels were assessed via immunoblotting. E–G, IPC-298, CO79, and A375 cells were treated with DMSO, 5 µmol/L A-485, 5 µmol/L MG-132, or their combination for 16 hours. SOX10 protein levels were assessed via immunoblotting. *, P < 0.05.
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.
