Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer

Abstract

Several lines of evidence indicate that during transformation epithelial cancer cells can acquire mesenchymal features via a process called epithelial-to-mesenchymal transition (EMT). This process endows cancer cells with increased invasive and migratory capacity, enabling tumour dissemination and metastasis. EMT is associated with a complex metabolic reprogramming, orchestrated by EMT transcription factors, which support the energy requirements of increased motility and growth in harsh environmental conditions. The discovery that mutations in metabolic genes such as FH, SDH and IDH activate EMT provided further evidence that EMT and metabolism are intertwined. In this review, we discuss the role of EMT in cancer and the underpinning metabolic reprogramming. We also put forward the hypothesis that, by altering chromatin structure and function, metabolic pathways engaged by EMT are necessary for its full activation.

Keywords: EMT; FH; IDH; SDH; cancer; epigenetics; metabolism; metastasis; mitochondrial metabolism.

Fig.1. EMT controls metabolic reprogramming

EMT transcription factors (EMT-TFs) control the expression of metabolic genes of different pathways such as glycolysis, lipid metabolism, and mitochondrial metabolism, and glutaminolysis. Specifically, EMT-TFs suppress the expression of fructose-1,6-bisphosphatase 1 (FBP1), fatty acid synthase (FASN), acetyl-coA carboxylase (ACC), nucleoside transporter, and pyruvate dehydrogenase kinase 4 (PDK4), whilst enhance the expression of dihydropyrimidine dehydrogenase (DPYD), glutaminase 1 (GLS1), enzymes of glutathione metabolism, cytochrome P450, aldehyde dehydrogenases, and glucose transporter 3 (GLUT3). Red dashed arrows indicate the metabolic nodes regulated by EMT-TFs. TCA=tricarboxylic acid cycle.

Fig.2. Metabolic genes control EMT.

Aberrant expression of metabolic enzymes of glycolysis (orange), lipid metabolism (purple), glutaminolysis (blue), mitochondrial metabolism (green), leads to EMT. Red dashed arrows indicate the link between specific metabolic pathway/metabolites and EMT. ACC=acetyl-CoA carboxylase; ACL=ATP citrate lyase; ACSL=acetyl-CoA synthetase; ALDOA=aldolase A; CaN=calcineurin A; CI-CV=respiratory chain complexes I-V; CoQ=coenzyme Q; CS=citrate synthase; CytC=cytochrome C; FBP1=fructose-1,6-bisphosphatase 1; FH=fumarate hydratase; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; GLS=glutaminase; IDH=isocitrate dehydrogenase; LDHA=lactic dehydrogenase A; PGI =phosphoglucose isomerase; PKM2=pyruvate kinase M2; SCD=steroyl-CoA desaturase; SDH=succinate dehydrogenase.

Fig.3. EMT activation by mutations in FH, SDH and IDH requires epigenetic reprogramming.

Schematic representation of how mitochondrial metabolites accumulated upon mutation of the indicated TCA cycle enzymes activate the EMT. A common pathway affected by these metabolites is the epigenetic suppression of a family of antimetastatic microRNAs, miR200, via the inhibition of histone demethylases (KDMs) and DNA demethylases (TETs). Of note, in the case of 2HG, the suppression of miR200 is indirect, and occurs via activation of Zeb1/2. See the text for more details. FH=fumarate hydratase; SDH=succinate dehydrogenase; IDH=isocitrate dehydrogenase.

Fig.4. Integration between oncogenic signalling, metabolic transformation, and epigenetic reprogramming during EMT

EMT requires the coordinated activation of multiple cellular processes, here represented as gears within a clockwork. Each of these components are essential for the full activation of EMT. As consequence, the inhibition of parts of this clockwork hampers the full activation of the EMT. For instance, inhibition of mutant IDH, or activation of PKA can block EMT. PKA=protein kinase A; IDH=isocitrate dehydrogenase.