Pamela Becherini1,2, Irene Caffa1,2, Francesco Piacente1,2,3, Patrizia Damonte1, Valerio G Vellone2,4, Mario Passalacqua3, Andrea Benzi3, Tommaso Bonfiglio1, Daniele Reverberi2, Amr Khalifa1, Moustafa Ghanem1, Ana Guijarro2, Luca Tagliafico1, Marzia Sucameli1, Angelica Persia1, Fiammetta Monacelli1,2, Michele Cea1,2, Santina Bruzzone3, Silvia Ravera5, Alessio Nencioni6,7. 1. Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy. 2. Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy. 3. Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy. 4. Department of Integrated, Surgical and Diagnostic Sciences (DISC), University of Genoa, L.go Rosanna Benzi 8, 16132, Genoa, Italy. 5. Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy. silvia.ravera@unige.it. 6. Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy. alessio.nencioni@unige.it. 7. Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy. alessio.nencioni@unige.it.
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.
BACKGROUND:Sirtuin 6 (SIRT6) is aNAD+-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 ofSIRT6 in BC cell metabolism and in mousepolyoma middle T antigen (PyMT)-driven mammary tumors. METHODS: We evaluated the effect of a heterozygous deletion ofSirt6 on tumor latency and survival ofmouse mammary tumor virus (MMTV)-PyMT mice. The effect ofSIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect ofSirt6 heterozygous deletion, ofSIRT6 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 ofMDA-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 asUQCRFS1, 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.
Entities:
Keywords:
Breast cancer; Cancer metabolism; Mammary tumorigenesis; Oxidative phosphorylation; SIRT6
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