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- Title
HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis.
- Authors
Emmons, Michael F.; Bennett, Richard L.; Riva, Alberto; Gupta, Kanchan; Carvalho, Larissa Anastasio Da Costa; 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.; Smalley, Keiran S. M.
- 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. The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.
- Subjects
BRAIN metastasis; MELANOMA; HISTONE acetyltransferase; NEURAL development; BINDING sites; BRAF genes
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43519-1