title: MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers.
abstract: Altered cellular metabolism is a fundamental adaptation of cancer during rapid proliferation as a result of growth factor overstimulation. We review different pathways involving metabolic alterations in cancers including aerobic glycolysis, pentose phosphate pathway, de novo fatty acid synthesis, and serine and glycine metabolism. Although oncoproteins, c-MYC, HIF1α and p53 are the major drivers of this metabolic reprogramming, post-transcriptional regulation by microRNAs (miR) also plays an important role in finely adjusting the requirement of the key metabolic enzymes underlying this metabolic reprogramming. We also combine the literature data on the miRNAs that potentially regulate 40 metabolic enzymes responsible for metabolic reprogramming in cancers, with additional miRs from computational prediction. Our analyses show that: (1) a metabolic enzyme is frequently regulated by multiple miRs, (2) confidence scores from prediction algorithms might be useful to help narrow down functional miR-mRNA interaction, which might be worth further experimental validation. By combining known and predicted interactions of oncogenic transcription factors (TFs) (c-MYC, HIF1α and p53), sterol regulatory element binding protein 1 (SREBP1), 40 metabolic enzymes, and regulatory miRs we have established one of the first reference maps for miRs and oncogenic TFs that regulate metabolic reprogramming in cancers. The combined network shows that glycolytic enzymes are linked to miRs via p53, c-MYC, HIF1α, whereas the genes in serine, glycine and one carbon metabolism are regulated via the c-MYC, as well as other regulatory organization that cannot be observed by investigating individual miRs, TFs, and target genes.
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Pannapa
authors.initials: P
authors.lastname: Pinweha
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Khanti
authors.initials: K
authors.lastname: Rattanapornsompong
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Integrative Computational BioScience (ICBS) Center, Mahidol University, Nakhon Pathom 73170, Thailand.
authors.forename: Varodom
authors.initials: V
authors.lastname: Charoensawan
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Sarawut
authors.initials: S
authors.lastname: Jitrapakdee
keywords: 2-HG, 2-hydroxyglutarate; ACC, acetyl-CoA carboxylase; ACL, ATP-citrate lyase; BRCA1, breast cancer type 1 susceptibility protein; Cancer; FAS, fatty acid synthase; FH, fumarate hydratase; G6PD, glucose-6-phosphate dehydrogenase; GDH, glutamate dehydrogenase; GLS, glutaminase; GLUT, glucose transporter; HIF1α, hypoxia inducible factor 1α; HK, hexokinase; IDH, isocitrate dehydrogenase; MCT, monocarboxylic acid transporter; ME, malic enzyme; Metabolism; MicroRNA; Oncogene; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PEPCK, phosphoenolpyruvate carboxykinase; PFK, phosphofructokinase; PGK, phosphoglycerate kinase (PGK); PHGDH, phosphoglycerate dehydrogenase; PKM, muscle-pyruvate kinase; PPP, pentose phosphate pathway; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SDH, succinate dehydrogenase; SHMT, serine hydroxymethyl transferase; SREBP1, sterol regulatory element binding protein 1; TCA, tricarboxylic acid; TFs, transcription factors; Transcriptional regulation network; c-MYC, V-myc avian myelocytomatosis viral oncogene homolog; miR/miRNA, LDH, lactate dehydrogenase micro RNA; p53, tumor protein p53