ACSS1-DEPENDENT ACETATE UTILIZATION REWIRES MITOCHONDRIAL METABOLISM TO SUPPORT TUMOR GROWTH

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell and Molecular Biology
Discipline
Biology
Biochemistry, Biophysics, and Structural Biology
Biology
Subject
acetate
acetyl-CoA
ACSS1
ACSS2
melanoma
mitochondria
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Copyright date
01/01/2024
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Author
Hlavaty, Sabina, I
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Abstract

Tumor development involves a variety of signaling and metabolic changes that promote cancer cell survival and proliferation, including under conditions of nutrient stress. Metabolic changes can include a shift to using alternative nutrient sources to support vital metabolic pathways, such as oxidative phosphorylation, fatty acid biosynthesis, and nucleotide biosynthesis. One important alternative nutrient source for many primary cancers is acetate. Circulating acetate levels in the serum are relatively low but can increase over ten-fold in response to changes in dietary behavior, such as excessive alcohol consumption. Furthermore, organs in the body have different basal acetate levels, resulting in variable nutrient availability at different tissue sites. Acetate can only be metabolized into acetyl-CoA by two enzymes: acetyl-CoA synthetase 1 and 2 (ACSS1 and ACSS2) which are localized to the mitochondria and cytosol, respectively. While ACSS2 has been extensively studied, the role of ACSS1 in cancer is largely unexplored. ACSS1-derived acetyl-CoA can enter the tricarboxylic acid (TCA) cycle to support mitochondrial metabolism. This dissertation therefore set out to evaluate the role of ACSS1-derived acetyl-CoA in melanoma growth and metabolism. We show that ACSS1 and ACSS2 are differentially expressed across cancer types. Melanoma cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism in vitro, and loss of ACSS1 expression suppresses acetate utilization for acetyl-CoA production. Furthermore, we identify a differential metabolic response in melanoma cells exposed to physiologically low and physiologically high levels of acetate. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to TCA cycle metabolites. Melanoma cells expressing ACSS1 have improved survival under hypoxia and nutrient stressed conditions, but only when acetate availability is maintained over time. ACSS1 knockdown also suppresses melanoma tumor growth in vivo. This study highlights a key role for ACSS1-derived acetyl-CoA metabolism for cancer growth, highlighting the potential for ACSS1-targeting therapies in melanoma.

Advisor
Schug, Zachary, T.
Date of degree
2024
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