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