title: The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells.
abstract: Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regulates glucose metabolism and promotes an oncogenic phenotype are not known. RUNX2 expression in luminal BC cells correlated with lower estrogen receptor-α (ERα) levels, anchorage-independent growth, expression of glycolytic genes, increased glucose uptake, and sensitivity to glucose starvation, but not to inhibitors of oxidative phosphorylation. Conversely, RUNX2 knockdown in triple-negative BC cells inhibited mammosphere formation and glucose dependence. RUNX2 knockdown resulted in lower LDHA, HK2, and GLUT1 glycolytic gene expression, but upregulation of pyruvate dehydrogenase-A1 (PDHA1) mRNA and enzymatic activity, which was consistent with lower glycolytic potential. The NAD-dependent histone deacetylase, SIRT6, a known tumor suppressor, was a critical regulator of these RUNX2-mediated metabolic changes. RUNX2 expression resulted in elevated pAkt, HK2, and PDHK1 glycolytic protein levels that were reduced by ectopic expression of SIRT6. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation (respiration). Overexpression of SIRT6 increased respiration in RUNX2-positive cells, but knockdown of SIRT6 in cells expressing low RUNX2 decreased respiration. RUNX2 repressed SIRT6 expression at both the transcriptional and post-translational levels and endogenous SIRT6 expression was lower in malignant BC tissues or cell lines that expressed high levels of RUNX2. These results support a hypothesis whereby RUNX2-mediated repression of the SIRT6 tumor suppressor regulates metabolic pathways that promote BC progression.
authors: Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Laboratory of Genitourinary Cancer Pathogenesis, NCI, Building 36/Room 1130, 37 Convent Drive, Bethesda, Maryland, 20814.
authors: Moran
authors: M
authors: Choe
authors: Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Jessica L
authors: JL
authors: Brusgard
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Saranya
authors: S
authors: Chumsri
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Lekhana
authors: L
authors: Bhandary
authors: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Pathology and the VA San Diego Healthcare System, University of California, San Diego, California, 92161.
authors: Xianfeng Frank
authors: XF
authors: Zhao
authors: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Song
authors: S
authors: Lu
authors: Department of Epidemiology & Public Health, The Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Olga G
authors: OG
authors: Goloubeva
authors: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Brian M
authors: BM
authors: Polster
authors: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Gary M
authors: GM
authors: Fiskum
authors: Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York, 11794.
authors: Geoffrey D
authors: GD
authors: Girnun
authors: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Myoung Sook
authors: MS
authors: Kim
authors: Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.|The Veteran's Health Administration Research & Development Service, Marlene & Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland.
authors: Antonino
authors: A
authors: Passaniti
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010085:Oxidative Phosphorylation; D037761:Sirtuins / Q000096:biosynthesis* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D009363:Neoplasm Proteins; C493709:RUNX2 protein, human; C516592:SIRT6 protein, human; D037761:Sirtuins; D005947:Glucose
keywords: BREAST CANCER; GLYCOLYSIS; METABOLISM; MITOCHONDRIAL RESPIRATION; TRANSCRIPTION