PXD017487

PXD017487 is an original dataset announced via ProteomeXchange.

Title	DGAT1 phosphoproteome and long-term proteome
Description	Enhanced fatty acid (FA) synthesis and uptake underpin the sustained membrane biogenesis and ATP production required for melanoma cell growth and division1-4. However, to thrive, melanoma cells must avoid a potential reduction in cell growth signalling, rampant reactive oxygen species (ROS) generation, and the build-up of toxic lipid species that can accompany excess free FA5. Here, we uncover and address the significance of frequent amplification and up-regulation of the Diacylglycerol O-acyltransferase 1 (DGAT1) gene in melanoma, whose encoded product catalyses the final step of Triacyglyceride (TAG) synthesis. Consistent with the classification of DGAT1 as an oncogene, we found that forced DGAT1 expression in p53 mutant zebrafish melanocytes was sufficient to induce melanoma, and accelerated melanoma progression initiated by co-expression of oncogenic BRAF or NRAS. Regarding DGAT1 function in human melanoma cells, its depletion, or alternatively pharmacological inhibition, suppressed mTOR-S6K signalling and increased levels of acyl carnitine species— FA derivatives that are the limiting substrate for FA oxidation (FAO). In turn, increased FAO induced mitochondrial malfunction, ROS generation, and lipid peroxidation. However, the resultant oxidative stress induced NRF2 and SESTRIN2 (SESN2) expression, which limited the extent of cell death. Conversely, DGAT1 over-expression enhanced mTOR-S6K signalling and cell growth, and protected against ROS, particularly in hypoxic conditions. Together, our data establish DGAT1 as a bona fide oncogene essential in melanoma cells for enabling FA accumulation.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:35:12.262.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chiara Francavilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-12 07:34:14	ID requested
1	2023-03-10 15:03:11	announced
⏵ 2	2023-11-14 08:35:13	announced	2023-11-14: Updated project metadata.

Wilcock DJ, Badrock AP, Wong CW, Owen R, Guerin M, Southam AD, Johnston H, Telfer BA, Fullwood P, Watson J, Ferguson H, Ferguson J, Lloyd GR, Jankevics A, Dunn WB, Wellbrock C, Lorigan P, Ceol C, Francavilla C, Smith MP, Hurlstone AFL, Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached. Cell Rep, 39(12):110995(2022) [pubmed]

submitter keyword: DGAT1 melanoma A229500 A375

Chiara Francavilla
contact affiliation	Division of Molecular and Cellular Function School of Biological Sciences The University of Manchester M139PT Manchester UK
contact email	chiara.francavilla@manchester.ac.uk
lab head
Chiara Francavilla
contact affiliation	University of Manchester
contact email	chiara.francavilla@manchester.ac.uk
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/2023/03/PXD017487

PRIDE project URI

• PRIDE
  1. PXD017487
     1. Label: PRIDE project
     2. Name: DGAT1 phosphoproteome and long-term proteome