Abstract 4461: Sirt6 deletion slows mouse mammary tumorigenesis

Abstract Studies show that the NAD+ dependent histone deacetylase Sirt6 exerts tumor suppressive effects in different tissues and organs by mechanisms that include the dampening of the Warburg effect and of Myc activity. In breast cancer (BC), Sirt6 was recently shown to blunt PI3K signaling and to reduce cancer stem cell like capacity in tumors with mutated PI3K. Here we sought define the effects of Sirt6 overexpression and of Sirt6 silencing in breast cancer cell lines, as well as the impact of a heterozygous Sirt6 deletion on polyoma middle T antigen (PyMT)-induced mouse mammary tumorigenesis, with the expectation of an accelerated mammary tumor development in PyMT+/-;Sirt6+/- as compared to PyMT+/-;Sirt6+/+ mice. SIRT6 was overexpressed in either wild type or catalytically inactive (H133Y) form, or silenced in BC cell lines and in non-tumorigenic MCF10A and HMLE cells, monitoring glycolytic enzyme activity (iHK, PFK, PK, LDH), lactate production, oxygen consumption rate, complex I, III, IV, and ATP synthase activity, and matrix metalloproteinase 9 (MMP9) expression. In vivo, we monitored the growth of MDA-MB-231 xenografts in which SIRT6 was silenced vs. control tumors. In addition, we crossed Sirt6+/- mice with MMTV-PyMT+/- mice (a kind gift of Dr. Thorsten Berger, University Health Network, Toronto, Canada) and comparatively monitored tumor latency and overall survival in PyMT+/-;Sirt6+/- vs. PyMT+/-;Sirt6+/+ mice. In cultured breast cancer cell lines, overexpression of catalytically active SIRT6 (but not of a catalytically inactive enzyme) reduced the activity of glycolytic enzymes as well as lactate production, while boosting OXPHOS and the ATP/AMP ratio. Opposite effects were obtained by SIRT6 silencing. Curiously, no effect of SIRT6 overexpression or of its silencing on glycolysis or OXPHOS was observed in non-tumorigenic mammary epithelial cells. SIRT6 was found to regulate MMP9 expression. Namely, in MDA-MB-231, SIRT6 overexpression increased, while SIRT6 silencing reduced MMP production. In vivo, subcutaneous xenografts of SIRT6-silenced MDA-MB-231 cells were found to grow slower than control cells. PyMT+/-;Sirt6+/- mice exhibited a markedly increased tumor latency and an increased overall survival as compared to the control PyMT+/-;Sirt6+/+ mice. The anticancer effect of Sirt6 heterozygous deletion did not reflect reduced glucose levels in Sirt6+/- mice, as the latter had normal blood glucose levels. In conclusion, our data show that reducing Sirt6 levels has antitumor effects in mouse breast cancer models, which would not be anticipated based on the available knowledge of Sirt6's biological role. In addition, by virtue of its ability to regulate MMP9 expression, SIRT6 could be a potential target for countering metastasis. Future studies should assess which molecular features predict the potential benefit of SIRT6 inhibition in breast cancer and test the anticancer activity of SIRT6 inhibitors. Citation Format: Pamela Becherini, Irene Caffa, Silvia Ravera, Patrizia Damonte, Francesco Piacente, Michele Cea, Antonia Cagnetta, Fiammetta Monacelli, Raul Mostoslavsky, Santina Bruzzone, Alberto Ballestrero, Patrizio Odetti, Alessio Nencioni. Sirt6 deletion slows mouse mammary tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4461.

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