PXD044471 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
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. |
Publication List
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] |
Keyword List
submitter keyword: Brain Metastasis,Melanoma, HDAC8, Acetylation |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD044471
- Label: PRIDE project
- Name: HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis