Figure 1 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

EP300 is commonly co-amplified with SOX10 in melanomas. A, The EP300 and SOX10 genes are located in close proximity on chromosome 22. B,EP300 and SOX10 amplification prevalence in different melanoma datasets [TCGA, Dana Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC)]. Acral patients from multiple datasets were combined (combined acral). Amplification levels were defined using GISTIC2.0. C,EP300 (left) and SOX10 (right) expressions were analyzed for each copy-number level, as defined by GISTIC2.0 (data from TCGA; Del, deletion; D, diploid; low, low-level amplification; high, high-level amplification). Statistical analysis is compared with diploid samples. D,EP300 and SOX10 copy numbers are positively correlated in melanoma cell lines (data from the CDM). E,EP300 copy number and expression are positively correlated in melanoma cell lines (left). SOX10 copy number and expression are positively correlated in melanoma cell lines (right; data CDM). F,EP300/SOX10 co-amplifications (>2 copies of EP300 and SOX10) are common in melanoma cell lines (data from CDM). *, 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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