The Evolving Landscape of Noncanonical Functions of Metabolic Enzymes in Cancer and Other Pathologies

Key pathological, including oncogenic, signaling pathways regulate the canonical functions of metabolic enzymes that serve cellular needs. Importantly, these also confer a large number to have noncanonical or nonmetabolic are referred as “moonlighting” functions. In this review, we highlight how aberrantly regulated with such activities play critical roles in governing wide spectrum instrumental activities, gene expression, cell-cycle progression, DNA repair, cell proliferation, survival, apoptosis, and tumor microenvironment remodeling, thereby promoting pathologic progression disease, cancer. Metabolic reprogramming response signals enables aberrant processes occur lead disease development. For cancer, elicit uncontrolled well adaptation by cells fluctuating availability nutrients oxygen occurs during oncogenic growth metastasis. modulating is not only permissive process meet needs for biosynthesis bioenergenesis, but plays causal role progression. instance, oncometabolites, through their actions modulate epigenetic pathways, promote malignancy (Cairns et al., 2011Cairns R.A. Harris I.S. Mak T.W. Regulation cancer metabolism.Nat. Rev. Cancer. 2011; 11: 85-95Crossref PubMed Scopus (2893) Google Scholar). Thus, metabolism can be intricately connected multiple products Functional regulation results from modulation activity certain noncanonical, non-metabolic, activities. The enhanced glycolysis pathway mitochondria regardless result Warburg effect, which distinct feature (Koppenol 2011Koppenol W.H. Bounds P.L. Dang C.V. Otto Warburg’s contributions current concepts 325-337Crossref (1508) Scholar; Wang 2018bWang Y. Xia Lu Z. features cells.Cancer Commun. 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Biological therapeutic potential cancer.Cancer Cell. 34: 186-195Abstract Full Text PDF (58) Aside mutations, spatially temporally regulated, harnessing pathological diseases functions, variety We herein summarize discuss knowledge about advances understanding moonlighting (Figure 1) remodeling disrupting (Table therapy cancer.Table 1Moonlighting Functions EnzymesMetabolic EnzymesNoncanonical FunctionsMetabolic FunctionsACLYglycolytic lipogenic ↑, β-catenin-dependent migration invasion, NFAT1-mediated HR repairACSS2TFEB-targeted growth-related memory-related neuronal HIF2-targeted ↑α-KGDHin complex KAT2A succinate expressionEnolase-1suppression transcription (FOXP3-E2 ↓, c-Myc ↓)FBP1/2suppression PRC2-mediated changes required HIF1/c-Myc-targeted ↓FHHIF1-targeted ATF2-targeted methylation-dependent ↑↓, repairGAPDHH2B mTOR ↓GDH1glucose uptake, survival ↑GMPSp53 downstream ↓HK2autophagy mitochondria-dependent apoptosis ↓HMGCLactivation BRAF-MEK-ERK signalingIMPDHhistone E2f proliferation ↓KHK-Ade novo nucleotide synthesis NRF2-dependent antioxidative stress ↑LDHAantioxidant Wnt target ↑MATHMOX1 methylation-regulated ↓MDH1p53-dependent arrest ↑MSRB2regulation progressionMTHFD1H3K27 acetylation transcriptionNME1/NME2suppression Raf-MEK-ERK (NME1), G protein activation (NME2)OGTgene ↑↓PCK1SREBP-dependent expressionPDCcell-cycle progression-related STAT5 SREBP-dependent AhR-targeted ↑PFKFB3/4DNA repair (PFKFB3), ATF4-targeted (PFKFB4) ↑PFKPactivation PI3K-AKT pathwayPGAM1DNA repairPGK1DNA replication autophagy aerobic ↑PKM2CCND1 MYC AhR/STAT3/ HIF1/C-Rel/ NRF2-targeted OCT4-targeted mitosis, cytokinesis exosome ectosomePTPSTGF-β secretion colon ↑SDH, IDH1/2 mutantshistone HIF1-targeted repairUGDHSNAI1 mRNA stability ↑ Open table new tab Gene alteration chromatin structure, resulting methylation at cytosine adenine residues modifications, methylation, acylation, phosphorylation, ubiquitylation, hydroxylation, glycation, serotonylation, glycosylation, sumoylation, ADP-ribosylation (Dai 2020Dai Ramesh V. 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