PXD012813

PXD012813 is an original dataset announced via ProteomeXchange.

Title	HDAC8 regulates escape from BRAF inhibitor therapy in Melanoma: IMAC Phosphoproteomics
Description	Melanoma cells are highly plastic and have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanoma cell lines and patient specimens to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia and UV-irradiation leads to an increase in histone deacetylase 8 (HDAC8) expression/activity, and in turn, the adoption of a drug-resistant, invasive phenotype. Systems level analyses using mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both non-selective and HDAC8-specific inhibitors enhancing the durability of response to BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors could represent an excellent strategy to limit the adaptation of melanoma cells to multiple stresses and therapeutic interventions, including BRAF-MEK inhibitor combinations.
HostingRepository	PRIDE
AnnounceDate	2020-07-07
AnnouncementXML	Submission_2020-07-06_22:01:32.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD012813
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Phospho; TMT6plex; Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-02-21 01:19:27	ID requested
⏵ 1	2020-07-06 22:01:33	announced

Emmons MF, Fai, ã, o-Flores F, Sharma R, Thapa R, Messina JL, Becker JC, Schadendorf D, Seto E, Sondak VK, Koomen JM, Chen YA, Lau EK, Wan L, Licht JD, Smalley KSM, HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy. Cancer Res, 79(11):2947-2961(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: Melanoma, BRAF, HDAC8

Keiran Smalley, PhD
contact affiliation	Tumor Biology and CutaTumor Biology and Cutaneous Oncology Melanoma Center of Excellence 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

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PRIDE project URI

• PRIDE
  1. PXD012813
     1. Label: PRIDE project
     2. Name: HDAC8 regulates escape from BRAF inhibitor therapy in Melanoma: IMAC Phosphoproteomics