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      The Two-Faced Role of SIRT6 in Cancer

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          Abstract

          Simple Summary

          Cancer therapy relies on the employment of different strategies aimed at inducing cancer cell death through different mechanisms, including DNA damage and apoptosis induction. One of the key regulators of these pathways is the epigenetic enzyme SIRT6, which has been shown to have a dichotomous function in cell fate determination and, consequently, cancer initiation and progression. In this review, we aim to summarize the current knowledge on the role of SIRT6 in cancer. We show that it can act as both tumor suppressor and promoter, even in the same cancer type, depending on the biological context. We then describe the most promising modulators of SIRT6 which, through enzyme activation or inhibition, may impair tumor growth. These molecules can also be used for the elucidation of SIRT6 function, thereby advancing the current knowledge on this crucial protein.

          Abstract

          Sirtuin 6 (SIRT6) is a NAD +-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.

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          Most cited references128

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          On the Origin of Cancer Cells

          O WARBURG (1956)
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            Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis.

            Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment. © 2012 Blackwell Publishing Ltd.
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              The emerging roles of forkhead box (Fox) proteins in cancer.

              Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. As a consequence, a loss or gain of Fox function can alter cell fate and promote tumorigenesis as well as cancer progression. Here we discuss the evidence that the deregulation of Fox family transcription factors has a crucial role in the development and progression of cancer, and evaluate the emerging role of Fox proteins as direct and indirect targets for therapeutic intervention, as well as biomarkers for predicting and monitoring treatment responses.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                08 March 2021
                March 2021
                : 13
                : 5
                : 1156
                Affiliations
                [1 ]Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK; francesco.fiorentino@ 123456chem.ox.ac.uk
                [2 ]Department of Precision Medicine, Università degli Studi della Campania “L. Vanvitelli”, 80138 Naples, Italy; vincenzo.carafa@ 123456unicampania.it (V.C.); gregorio.favale@ 123456unicampania.it (G.F.)
                [3 ]Department of Drug Chemistry & Technologies, Sapienza University of Rome, P. le A Moro 5, 00185 Rome, Italy
                Author notes
                [* ]Correspondence: lucia.altucci@ 123456unicampania.it (L.A.); antonello.mai@ 123456uniroma1.it (A.M.); dante.rotili@ 123456uniroma1.it (D.R.); Tel.: +39-081-5667569 (L.A.); +39-06-49913392 (A.M.); +39-06-49913237 (D.R.)
                [†]

                Co-First Authors.

                Author information
                https://orcid.org/0000-0003-3550-1860
                https://orcid.org/0000-0002-7312-5387
                https://orcid.org/0000-0001-9176-2382
                https://orcid.org/0000-0002-8428-8763
                Article
                cancers-13-01156
                10.3390/cancers13051156
                7962659
                33800266
                c74085a0-613c-4fa0-bb75-f50858430631
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 January 2021
                : 03 March 2021
                Categories
                Review

                nad+-dependent deacylases,cell death modulation,sirt6 modulators,cancer,epigenetics

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