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Data from p300 KAT Regulates SOX10 Stability and Function in Human Melanoma

Version 2 2024-09-28, 16:20
Version 1 2024-08-01, 15:20
Posted on 2024-09-28 - 16:20
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.

Significance:

The p300 KAT inhibitor A-485 blocks SOX10-dependent proliferation and SOX10-independent invasion in hard-to-treat melanoma cells.

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Cancer Research Communications

AUTHORS (9)

Aaron Waddell
Nicole Grbic
Kassidy Leibowitz
William Austin Wyant
Sabah Choudhury
Kihyun Park
Marianne Collard
Philip A. Cole
Rhoda M. Alani

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