Figure 2 from p300 KAT Regulates SOX10 Stability and Function in Human Melanoma

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posted on 2025-03-28, 22:24 authored by Aaron Waddell, Nicole Grbic, Kassidy Leibowitz, William Austin Wyant, Sabah Choudhury, Kihyun Park, Marianne Collard, Philip A. Cole, Rhoda M. Alani

SOX10 signaling requires p300 KAT activity. (A) A panel of melanoma cell lines were treated with DMSO (D) or 5 µmol/L A-485 (A) for 24 hours. SOX10, MITF, and DCT protein levels were assessed via immunoblotting. B, A panel of EP300/SOX10 co-amplified melanoma cell lines were treated with DMSO (D) or 5 µmol/L A-485 (A) for 24 hours. MITF and DCT expressions were assessed via RT-qPCR. C,MITF, SCD, and MYC expressions were downregulated by SOX10 KD in A375 cells. D, A panel of melanoma cell lines without EP300/SOX10 co-amplifications were treated with DMSO (D) or 5 µmol/L A-485 (A) for 24 hours. MITF, SCD, and MYC expressions were assessed via RT-qPCR. *, P < 0.05; **, P < 0.005; ***, P < 0.0005.

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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.

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Keywords

Skin Cancers Melanoma Epigenetics Gene Regulation Genome Biology Comparative transcriptomics Small Molecule Agents Epigenetic-targeted agents

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CC BY