Janus-faced role of SIRT1 in tumorigenesis

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Abstract

Silent mating type information regulation 1 (Sirtuin 1; SIRT1) has been reported to regulate various physiological events, such as aging and metabolism, via deacetylation of histone and nonhistone proteins. Notably, cumulative evidence supports the notion that SIRT1 has a Janus-faced role in tumorigenesis. SIRT1 contributes to anti-inflammation, genomic stability, and cancer cell death, and hence it has tumor-suppressor properties. On the other hand, SIRT1 can stimulate oncogenic signaling pathways and can create a tumor microenvironment favorable to growth and survival of cancer cells. Such dual functions of SIRT1 may be determined, at least in part, by its subcellular localization. Interestingly, SIRT1 displays differential localization in normal cells and cancer cells, which in turn may affect the substrate specificity for its deacetylase activity.

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Most cited references 71

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Mammalian sirtuins: biological insights and disease relevance.

Marcia Haigis, David A Sinclair (2010)

Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

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Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.

Aparna Purushotham, Thaddeus Schug, Qing Fang Xu … (2009)

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.

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Negative control of p53 by Sir2alpha promotes cell survival under stress.

J. Luo, A Y Nikolaev, S. Imai … (2001)

The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Ann N Y Acad Sci

Journal ID (iso-abbrev): Ann. N. Y. Acad. Sci

Journal ID (publisher-id): nyas

Title: Annals of the New York Academy of Sciences

Publisher: Blackwell Publishing Inc (Malden, USA )

ISSN (Print): 0077-8923

ISSN (Electronic): 1749-6632

Publication date (Print): October 2012

Publication date (Electronic): 10 October 2012

Volume: 1271

Issue: 1

Pages: 10-19

Affiliations

[1 ]Tumor Microenvironment Global Core Research Center, College of Pharmacy Seoul, South Korea

[2 ]Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Sciences and Technology Seoul, South Korea

[3 ]Cancer Research Institute, Seoul National University Seoul, South Korea

Author notes

Address for correspondence: Young-Joon Surh, Ph.D., College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea. surh@ 123456plaza.snu.ac.kr

Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms

Article

DOI: 10.1111/j.1749-6632.2012.06762.x

PMC ID: 3499659

PubMed ID: 23050959

SO-VID: 6f4236d3-e8b1-405b-9363-e6ecfe0c0d01

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Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Janus-faced role of SIRT1 in tumorigenesis

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Cancer Metabolism

Most cited references 71

Mammalian sirtuins: biological insights and disease relevance.

Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.

Negative control of p53 by Sir2alpha promotes cell survival under stress.

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