HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis

Michael F. Emmons, Richard L. Bennett, Alberto Riva, Kanchan Gupta, Larissa Anastasio Da Costa Carvalho, Chao Zhang, Robert Macaulay, Daphne Dupéré-Richér, Bin Fang, Edward Seto, John M. Koomen, Jiannong Li, Y. Ann Chen, Peter A. Forsyth, Jonathan D. Licht and Keiran S. M. Smalley ()
Additional contact information
Michael F. Emmons: Moffitt Cancer Center
Richard L. Bennett: UF Health Cancer Center
Alberto Riva: University of Florida
Kanchan Gupta: UF Health Cancer Center
Larissa Anastasio Da Costa Carvalho: Moffitt Cancer Center
Chao Zhang: Moffitt Cancer Center
Robert Macaulay: Moffitt Cancer Center
Daphne Dupéré-Richér: UF Health Cancer Center
Bin Fang: Moffitt Cancer Center
Edward Seto: George Washington University
John M. Koomen: Moffitt Cancer Center
Jiannong Li: Moffitt Cancer Center
Y. Ann Chen: Moffitt Cancer Center
Peter A. Forsyth: Moffitt Cancer Center
Jonathan D. Licht: UF Health Cancer Center
Keiran S. M. Smalley: Moffitt Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis.

Date: 2023
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DOI: 10.1038/s41467-023-43519-1

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