%0 Preprint
%T p300 KAT regulates SOX10 stability and function in human melanoma.
%A Waddell A
%A Grbic N
%A Leibowitz K
%A Wyant WA
%A Choudhury S
%A Park K
%A Collard M
%A Cole PA
%A Alani RM
%J bioRxiv
%V 0
%N 0
%D 2024 Feb 23
%M 38469149
暂无%R 10.1101/2024.02.20.581224
%X SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while 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. Here, 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.