Dataset Information

DGAT1 phosphoproteome and long-term proteome

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture

DISEASE(S): Melanoma

SUBMITTER: Chiara Francavilla

LAB HEAD: Chiara Francavilla

PROVIDER: PXD017487 | Pride | 2023-03-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20190618_CF_COLLAB_Dan_A375_SILAC_0_30_120_STY_01_01.raw	Raw
	20190618_CF_COLLAB_Dan_A375_SILAC_0_30_120_STY_01_02.raw	Raw
	20190618_CF_COLLAB_Dan_A375_SILAC_0_30_120_STY_02_01.raw	Raw
	20190618_CF_COLLAB_Dan_A375_SILAC_0_30_120_STY_02_02.raw	Raw
	20190618_CF_COLLAB_Dan_A375_SILAC_0_30_120_STY_03_01.raw	Raw

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Publications

Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.

Wilcock Daniel J DJ Badrock Andrew P AP Wong Chun W CW Owen Rhys R Guerin Melissa M Southam Andrew D AD Johnston Hannah H Telfer Brian A BA Fullwood Paul P Watson Joanne J Ferguson Harriet H Ferguson Jennifer J Lloyd Gavin R GR Jankevics Andris A Dunn Warwick B WB Wellbrock Claudia C Lorigan Paul P Ceol Craig C Francavilla Chiara C Smith Michael P MP Hurlstone Adam F L AFL

Cell reports 20220601 12

Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzym ...[more]

PMID: 35732120

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