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

Authors

• Michael F. Emmons, Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Richard L. Bennett, UF Health Cancer Center, 2033 Mowry Road, University of Florida, Gainesville, FL, 32610, USA.
• Alberto Riva, Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, 2033 Mowry Road, Gainesville, FL, 32610, USA.
• Kanchan Gupta, UF Health Cancer Center, 2033 Mowry Road, University of Florida, Gainesville, FL, 32610, USA.
• Larissa Anastasio Carvalho, Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Chao Zhang, Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Robert Macaulay, Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Daphne Dupéré-Richér, UF Health Cancer Center, 2033 Mowry Road, University of Florida, Gainesville, FL, 32610, USA.
• Bin Fang, Proteomics & Metabolomics Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Edward Seto, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, George Washington Cancer Center, George Washington University, 2300 Eye Street, Washington, DC, 20037, USA.
• John M. Koomen, Department of Molecular Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Jiannong Li, Department of Bioinformatics and Biostatistics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Y Ann Chen, Department of Bioinformatics and Biostatistics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Peter A. Forsyth, Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
• Jonathan D. Licht, UF Health Cancer Center, 2033 Mowry Road, University of Florida, Gainesville, FL, 32610, USA.
• Keiran S. Smalley, Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA. keiran.smalley@moffitt.org.

Document Type

Journal Article

Publication Date

11-29-2023

Journal

Nature communications

Volume

14

Issue

1

DOI

10.1038/s41467-023-43519-1

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.

APA Citation

Emmons, Michael F.; Bennett, Richard L.; Riva, Alberto; Gupta, Kanchan; Carvalho, Larissa Anastasio; Zhang, Chao; Macaulay, Robert; Dupéré-Richér, Daphne; Fang, Bin; Seto, Edward; Koomen, John M.; Li, Jiannong; Chen, Y Ann; Forsyth, Peter A.; Licht, Jonathan D.; and Smalley, Keiran S., "HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis" (2023). GW Authored Works. Paper 3749.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3749

Department

Biochemistry and Molecular Medicine