The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells

Moran Choe, Jessica L. Brusgard, Saranya Chumsri, Lekhana Bhandary, Xianfeng Frank Zhao, Song Lu, Olga G. Goloubeva, Brian M. Polster, Gary M. Fiskum, Geoffrey D. Girnun, Myoung Sook Kim, Antonino Passaniti

Research output: Contribution to journalArticle

29 Scopus citations

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. J. Cell. Biochem. 116: 2210-2226, 2015.

Original languageEnglish (US)
Pages (from-to)2210-2226
Number of pages17
JournalJournal of Cellular Biochemistry
Volume116
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Keywords

  • B REAST C ANCER
  • G LYCOLYSIS
  • M ETABOLISM
  • M ITOCHONDRIAL R ESPIRATION
  • T RANSCRIPTION

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Choe, M., Brusgard, J. L., Chumsri, S., Bhandary, L., Zhao, X. F., Lu, S., Goloubeva, O. G., Polster, B. M., Fiskum, G. M., Girnun, G. D., Kim, M. S., & Passaniti, A. (2015). The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells. Journal of Cellular Biochemistry, 116(10), 2210-2226. https://doi.org/10.1002/jcb.25171