PXD044471

PXD044471 is an original dataset announced via ProteomeXchange.

Title	HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis
Description	Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a gene expression signature associated with a neural crest-stem cell like state (NCSC) and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion, resistance to stress and the development of MBM. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.
HostingRepository	PRIDE
AnnounceDate	2024-04-02
AnnouncementXML	Submission_2024-04-02_06:44:16.536.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Brassica oleracea var. botrytis (Cauliflower); NCBI TaxID: 3715; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-09 19:13:41	ID requested
1	2023-09-26 11:05:41	announced
⏵ 2	2024-04-02 06:44:17	announced	2024-04-02: Updated project metadata.

10.1038/s41467-023-43519-1;

Emmons MF, Bennett RL, Riva A, Gupta K, Carvalho LADC, Zhang C, Macaulay R, Dup, é, r, é, -Rich, é, r D, Fang B, Seto E, Koomen JM, Li J, Chen YA, Forsyth PA, Licht JD, Smalley KSM, HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis. Nat Commun, 14(1):7759(2023) [pubmed]

submitter keyword: Brain Metastasis,Melanoma, HDAC8, Acetylation

Keiran Smalley
contact affiliation	Cutaneous Oncology/Tumor Biology Moffitt Cancer Center Tampa, FL, USA
contact email	keiran.smalley@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/09/PXD044471

PRIDE project URI

• PRIDE
  1. PXD044471
     1. Label: PRIDE project
     2. Name: HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis