Snail augments fatty acid oxidation by suppression of mitochondrial ACC2 during cancer progression

Abstract

Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial–mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial–mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.

New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis

“…Given that TGFβ1-induced activation of Smad3 is also a key signaling event leading to EMT, this study also suggests that FAO depression may occur secondary or in parallel to EMT. Supporting this, it has been reported that upregulation of Snail, a major regulator of EMT, correlated with the downregulation of critical genes involved in FAO expression in hepatocellular carcinomas (Tanaka et al, 2013); pharmacological inhibition of FAO reverses Snail-mediated metabolic reprogramming in vivo and progression of breast cancer (Yang et al, 2020). Future studies are needed to elucidate the role of EMT in the regulation of FAO or other metabolic alteration in the kidney after fibrotic injuries.…”

Breast Cancer Subtypes Underlying EMT-Mediated Catabolic Metabolism

“…In glucose-deficient conditions, which represent the metabolic status of the metastatic procedure, Snail specifically activates catabolic reprogramming. We have reported that Snail directly suppresses PFKP and ACC2 transcription, thereby switching the glycolytic flux into the PPP to enhance NADPH generation and stimulate oxidative phosphorylation via FAO, respectively [16,18]. ACC2 levels varied among breast cancer molecular subtypes in clinical samples, in an inverse relation to Snail with a reliance on p53 status.…”

“…The basal-like subtype shows a higher p53-loss rate along with increased Snail abundance than do the luminal subtypes (mainly p53 wild type) [18,61,66]. As the triple negative breast cancers (TNBC) have an aggressive clinical course and lack treatment options, there have been various attempts to unravel their pathogenesis.…”

“…The ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH) are essential catabolic metabolites under starved environment, and are controlled by interconnected glycolysis, gluconeogenesis, pentose phosphate pathway (PPP), and mitochondrial activity such as fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycles ( Figure 1). Recently, several metabolic enzymes have been identified as target genes of Snail transcriptional repressor including phosphofructokinase, platelet (PFKP), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase (ACC2) [16][17][18]. Snail repressor directly binds to the E-boxes located in proximal promoter of those target genes and Snail abundance is inversely correlated [16][17][18].…”

“…Recently, several metabolic enzymes have been identified as target genes of Snail transcriptional repressor including phosphofructokinase, platelet (PFKP), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase (ACC2) [16][17][18]. Snail repressor directly binds to the E-boxes located in proximal promoter of those target genes and Snail abundance is inversely correlated [16][17][18]. Interestingly, these Snail target genes are critical enzymes involving NADPH and ATP generation under glucose-starved environment, supporting the important role of Snail in catabolic metabolism during metastatic cancer progression.…”