Dgat1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

Abstract

Metabolic reprogramming is one of eight hallmarks of cancer; altered lipid metabolism such as enhanced fatty acid (FA) synthesis and uptake support the membrane biogenesis and ATP requirements for melanoma cell growth and division. As yet, few druggable oncoproteins directly responsible for altered metabolism in cancer cells have been identified. To thrive, however, cancer cells must avoid the reduction in cell growth signalling and generation of toxic lipid peroxides that ordinarily accompany excess free FA. Here, we have uncovered the frequent up- regulation and amplification in melanoma of the enzyme Diacylglycerol O- acyltransferase 1 (DGAT1). DGAT1 catalyses triacylglyceride synthesis, the final step in lipid droplet formation, which allow cancer cells to tolerate excess FA. Using zebrafish transgenesis, we found forced Dgat1 expression in melanocytes accelerated melanoma development driven by oncogenic BRAF or NRAS. Strikingly, in p53 mutant zebrafish melanocytes forced Dgat1 expression alone induced melanoma formation. Utilising both in vitro and in vivo models we found that the pro-oncogenic activity of DGAT1 was mediated through the stimulation of mTOR- S6K, signalling melanoma cell growth and protecting melanoma cells from cell death induced by oxidative stress and lipotoxicity. Inhibition of DGAT1 leads to a decrease in mTOR signalling through S6K and increased production of toxic metabolites leading to a loss of mitochondrial membrane potential and an increase in reactive oxygen species, ultimately leading to melanoma cell death. Together, our data identifies DGAT1 as a bona fide oncogene that stimulates cell growth and suppresses oxidative stress while enabling fatty acid accumulation and thus, a putative therapeutic target in melanoma.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Paul Lorigan (Supervisor), Adam Hurlstone (Supervisor) & Claudia Wellbrock (Supervisor)