Acetate Dependence of Tumors

By S. Comerford, Zhiguang Huang, Xinlin Du, Yun Wang, L. Cai, A. Witkiewicz, Holly Walters, M. Tantawy, A. Fu, H. Manning and 4 more. Cell, 2014

629 citations recorded by the source corpus.

SUMMARY Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation and the regulation of gene expression. How highly glycolytic or hypoxic tumors are able to produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions remains poorly understood. Here we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

Subfields: Cancer Research, Physiology

View Paper: https://www.semanticscholar.org/paper/16420fd8b9bb5adcd46b5447ad81cd92b40d2a37

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Citations in the corpus

Mitochondria and Cancer (2016, background): “This replenishment of the TCA cycle 4C units is termed anaplerosis and can occur through carboxylation of pyruvate or catabolism of glutamine and other amino acids (Comerford et al., 2014; DeBerardinis et al., 2007; Fan et al., 2009; Mashimo et al., 2014; Yuneva et al., 2007).”
Lipid metabolism reprogramming and its potential targets in cancer (2018, background): “When each isoform was genetically knocked down in HepG2 cells, only ACSS2 down-regulation dramatically suppressed acetate-mediated lipid synthesis and histone modification [72].”
Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “from Tu’s lab [98] illustrates that in highly glycolytic or hypoxic cancer cells, acetate is captured as a carbon source”
Acetate is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases (2014, positive): “The current work and that of Comerford et al. (2014) underscores the value of in vivo studies in cancermetabolism.”
Fundamentals of cancer metabolism (2016, background): “Although a major function of the mitochondria is to provide acetyl-CoA to the cell, cancer cells can also use acetate to support cell growth and survival during metabolic stress (hypoxia or nutrient deprivation) (96, 171).”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “An interesting adaptation of cancer cells is the utilization of acetate as a fuel (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright and Simone, 2016; Yoshii et al., 2015).”
Targeting Metabolism for Cancer Therapy (2017, background): “Some cancers are nevertheless dependent on expression of acetyl-CoA synthetase 2 (ACSS2), the cytosolic enzyme that allows cells to synthesize acetyl-CoA from acetate, making this represents a potential therapeutic target (Comerford et al., 2014; Schug et al., 2015).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…acetate is mediated by acyl-CoA synthetase shortchain family members (ACSSs), including ACSS1 and ACSS3 in mitochondria and ACSS2 in the cytoplasm and nucleus (Luong et al., 2000; Fujino et al., 2001; PerezChacon et al., 2009; Ariyannur et al., 2010; Choudhary et al., 2014; Comerford et al., 2014).”