Research Papers:

Enhancement of NAD+-dependent SIRT1 deacetylase activity by methylselenocysteine resets the circadian clock in carcinogen-treated mammary epithelial cells

Mingzhu Fang _, Wei-Ren Guo, Yongil Park, Hwan-Goo Kang and Helmut Zarbl

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Oncotarget. 2015; 6:42879-42891. https://doi.org/10.18632/oncotarget.6002

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Mingzhu Fang1,2,3,4,5, Wei-Ren Guo1, Youngil Park6, Hwan-Goo Kang6, Helmut Zarbl1,2,3,4,5

1Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

2School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

3Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

4NIEHS Center for Environmental Exposures and Disease, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

5Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

6Veterinary Drugs & Biologics Division, Animal and Plant Quarantine Agency, Anyang 430-757, Republic of Korea

Correspondence to:

Mingzhu Fang, e-mail: [email protected]

Keywords: circadian clock, N-methyl-N-nitrosourea, methylselenocysteine, period 2, SIRT1

Received: August 31, 2015     Accepted: October 13, 2015     Published: October 26, 2015


We previously reported that dietary methylselenocysteine (MSC) inhibits N-methyl-N-nitrosourea (NMU)-induced mammary tumorigenesis by resetting circadian gene expression disrupted by the carcinogen at the early stage of tumorigenesis. To investigate the underlying mechanism, we developed a circadian reporter system comprised of human mammary epithelial cells with a luciferase reporter driven by the promoter of human PERIOD 2 (PER2), a core circadian gene. In this in vitro model, NMU disrupted cellular circadian rhythm in a pattern similar to that observed with SIRT1-specific inhibitors; in contrast, MSC restored the circadian rhythms disrupted by NMU and protected against SIRT1 inhibitors. Moreover, NMU inhibited intracellular NAD+/NADH ratio and reduced NAD+-dependent SIRT1 activity in a dose-dependent manner, while MSC restored NAD+/NADH and SIRT1 activity in the NMU-treated cells, indicating that the NAD+-SIRT1 pathway was targeted by NMU and MSC. In rat mammary tissue, a carcinogenic dose of NMU also disrupted NAD+/NADH oscillations and decreased SIRT1 activity; dietary MSC restored NAD+/NADH oscillations and increased SIRT1 activity in the mammary glands of NMU-treated rats. MSC-induced SIRT1 activity was correlated with decreased acetylation of BMAL1 and increased acetylation of histone 3 lysine 9 at the Per2 promoter E-Box in mammary tissue. Changes in SIRT1 activity were temporally correlated with loss or restoration of rhythmic Per2 mRNA expression in NMU-treated or MSC-rescued rat mammary glands, respectively. Together with our previous findings, these results suggest that enhancement of NAD+-dependent SIRT1 activity contributes to the chemopreventive efficacy of MSC by restoring epigenetic regulation of circadian gene expression at early stages of mammary tumorigenesis.

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