Abstract
BackgroundSirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors.MethodsWe evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration.ResultsThe heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice.ConclusionsVia its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.
Highlights
Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism
SIRT6 downregulation slows breast cancer (BC) progression in MMTVPyMT mouse model To define the role of SIRT6 in mammary carcinogenesis, we utilized transgenic mice expressing the polyoma middle T antigen (PyMT) under the mammary tumor virus (MMTV) promoter, which is an established animal model of human BC [29, 30]
We crossed MMTV-PyMT+/− male mice with Sirt6+/− female animals and compared tumor latency and mouse survival between MMTV-PyMT+/−; Sirt6+/+ and MMTV-PyMT+/−; Sirt6+/− mice
Summary
Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. There remains a crucial need to enhance our understanding of BC biology and to define new viable therapeutic targets for this condition. Neoplastic transformation involves a metabolic reprogramming to support the biosynthesis of macromolecules that are needed for cell division and growth [2]. Such changes are similar to those occurring in highly proliferative normal cells during embryogenesis, wound healing, and immune response [3]. Cancer cells acquire mutations in oncogenes and in tumor suppressors that enhance glycolysis and anabolic metabolism in the absence of external signals (Warburg effect) [4]. While glycolysis represents a source of molecules necessary for biomass enhancement, OXPHOS appears to underlie anabolic metabolism, cell proliferation, cancer stemness, and metastasis [3]
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