SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice

Abstract

Background 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. 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. Methods We 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. Results The 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. Conclusions Via 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.

Metabolic Changes in Maternal and Cord Blood in One Case of Pregnancy-Associated Breast Cancer Seen by Fluorescence Lifetime Imaging Microscopy

“…It was reported that NAD (NAD + and NADH) concentrations decreased both in blood and tissues (including liver, kidney, stomach, cerebrum, lung, spleen, and large and small intestine) when mice were fed a NiA-free diet [26]. It was also reported that NADH together with SIRT protein promote tumorigenesis [27]. It could be assumed that PABC disease influences NAD(P)H in blood as well.…”

Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer

“…As described above, OXPHOS plays a role in the pathophysiology of cancers including breast cancer (Zu and Guppy, 2004;Vaupel and Mayer, 2012;Ippolito et al, 2016;Ashton et al, 2018;Ikeda et al, 2019;Schöpf, et al, 2020;Takayama et al, 2020;Becherini et al, 2021). In fact, overexpression of mitochondrial OXPHOSrelated proteins including cytochrome c oxidase subunit 4 (COX4) has been identified in breast cancer cells (Calderón-González et al, 2015).…”

The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy

“…PDHC is essential for glucose oxidation through its ability to promote a switch from the glycolytic to the oxidative pathway and the subsequent use of substrates through the respiratory chain in mitochondria. PDHC catalyzes the oxidative decarboxylation of pyruvate, yielding NADH and acetyl-CoA, key molecules for mitochondrial ATP generation ( 48 ). During sepsis, the downregulation of PDHC might contribute to energy metabolism disturbances by impairing the capacity of mitochondria for energy production.…”