Dietary Methylselenocysteine and Epigenetic Regulation of Circadian Gene Expression

  • Helmut Zarbl
  • Mingzhu FangEmail author
Reference work entry


Selenium (Se) is an essential trace element. Methylselenocysteine (MSC) is an organic form of selenium obtained primarily through dietary ingestion. Selenium, especially MSC, showed significant inhibitory effect on mammary tumorigenesis, especially at early stages, in carcinogen-induced rat mammary tumor models. However the underlying mechanisms are not fully understood. Accumulating evidence indicates that disruption of circadian rhythm by shift work or jet lag increases the risk of breast, prostate, and colon cancers. About 10% of genes, including many genes involved in hormone signaling and DNA damage response and repair (DDRR), are under circadian control and as a result show significant oscillation in expression across the day. Recent mechanism studies demonstrated that MSC restored and enhanced circadian expression of major clock genes, especially Period 2 (Per2), and circadian-controlled genes to inhibit mammary tumorigenesis induced by carcinogens in rats. Moreover, MSC restores and enhances circadian gene expression by increasing NAD+/NADH and SIRT1 activity and modulated acetylation of circadian regulatory protein, BMAL1, and histone 3 associated with Per2 gene promoter. This chapter will focus on how the dietary chemopreventive regimen of MSC epigenetically modulates the circadian rhythm at molecular level and how it contributes to its chemopreventive activity.


Methylselenocysteine Nitrosomethylurea Chemoprevention Breast cancer Circadian rhythm NAD+ SIRT1 activity Acetylation Period 2 DNA damage response and repair 

List of Abbreviations


Acetylated BMAL1


Acetylated histone 3 lysine 9


Circadian-controlled gene


Circadian (clock) gene


DNA damage response and repair


Fisher 344 rat strain






Suprachiasmatic nucleus


  1. Akerstedt T, Knutsson A, Narusyte J et al (2015) Night work and breast cancer in women: a Swedish cohort study. BMJ Open 5:e008127CrossRefGoogle Scholar
  2. Balsalobre A (2002) Clock genes in mammalian peripheral tissues. Cell Tissue Res 309:193–199CrossRefGoogle Scholar
  3. De Miranda JX, Andrade fde O, Conti A et al (2014) Effects of selenium compounds on proliferation and epigenetic marks of breast cancer cells. J Trace Elem Med Biol 28:486–491CrossRefGoogle Scholar
  4. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508CrossRefGoogle Scholar
  5. Druzhyna N, Smulson ME, Ledoux SP et al (2000) Poly(ADP-ribose) polymerase facilitates the repair of N-methylpurines in mitochondrial DNA. Diabetes 49:1849–1855CrossRefGoogle Scholar
  6. El-Bayoumy K, Sinha R, Pinto J et al (2006) Cancer chemoprevention by garlic and garlic-containing sulfur and selenium compounds. J Nutr 136:864S–869SCrossRefGoogle Scholar
  7. Etchegaray JP, Lee C, Wade P et al (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182CrossRefGoogle Scholar
  8. Fang MZ, Zhang X, Zarbl H (2010) Methylselenocysteine resets the rhythmic expression of circadian and growth-regulatory genes disrupted by nitrosomethylurea in vivo. Cancer Prev Res (Phila) 3:640–652CrossRefGoogle Scholar
  9. Fang MZ, Ohman-Strickland P, Kelly-Mcneil K et al (2015a) Sleep interruption associated with house staff work schedules alters circadian gene expression. Sleep Med 16:1388–1394CrossRefGoogle Scholar
  10. Fang M, Guo WR, Park Y et al (2015b) Enhancement of NAD(+)-dependent SIRT1 deacetylase activity by methylselenocysteine resets the circadian clock in carcinogen-treated mammary epithelial cells. Oncotarget 6:42879–42891PubMedPubMedCentralGoogle Scholar
  11. Fang M, Ohman-Strickland PA, Kang H-G et al (2017) Uncoupling genotoxic stress responses from circadian control increases susceptibility to mammary carcinogenesis. Oncotarget. 16;8:32752–32768Google Scholar
  12. Fiala ES, Staretz ME, Pandya GA et al (1998) Inhibition of DNA cytosine methyltransferase by chemopreventive selenium compounds, determined by an improved assay for DNA cytosine methyltransferase and DNA cytosine methylation. Carcinogenesis 19:597–604CrossRefGoogle Scholar
  13. Fu L, Kettner NM (2013) The circadian clock in cancer development and therapy. Prog Mol Biol Transl Sci 119:221–282CrossRefGoogle Scholar
  14. Ganther HE (1999) Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20:1657–1666CrossRefGoogle Scholar
  15. Gery S, Virk RK, Chumakov K et al (2007) The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 26:7916–7920CrossRefGoogle Scholar
  16. Haus EL, Smolensky MH (2013) Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep Med Rev 17:273–284CrossRefGoogle Scholar
  17. Hazane-Puch F, Arnaud J, Trocme C et al (2016) Sodium selenite decreased HDAC activity, cell proliferation and induced apoptosis in three human glioblastoma cells. Anti Cancer Agents Med Chem 16:490–500CrossRefGoogle Scholar
  18. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13:225–238CrossRefGoogle Scholar
  19. IARC (2010) Painting firefighting, and shiftwork. IARC Monogr Eval Carcinog Risks Hum 98:563–764Google Scholar
  20. Jackson MI, Combs GF Jr (2008) Selenium and anticarcinogenesis: underlying mechanisms. Curr Opin Clin Nutr Metab Care 11:718–726CrossRefGoogle Scholar
  21. Knutsson A, Alfredsson L, Karlsson B et al (2013) Breast cancer among shift workers: results of the WOLF longitudinal cohort study. Scand J Work Environ Health 39:170–177CrossRefGoogle Scholar
  22. Lavu S, Boss O, Elliott PJ et al (2008) Sirtuins–novel therapeutic targets to treat age-associated diseases. Nat Rev Drug Discov 7:841–853CrossRefGoogle Scholar
  23. Nakahata Y, Kaluzova M, Grimaldi B et al (2008) The NAD+−dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340CrossRefGoogle Scholar
  24. Parent ME, El-Zein M, Rousseau MC et al (2012) Night work and the risk of cancer among men. Am J Epidemiol 176(9):751CrossRefGoogle Scholar
  25. Peyrot F, Ducrocq C (2008) Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species. J Pineal Res 45:235–246CrossRefGoogle Scholar
  26. Ramsey KM, Yoshino J, Brace CS et al (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324:651–654CrossRefGoogle Scholar
  27. Rana S, Mahmood S (2010) Circadian rhythm and its role in malignancy. J Circadian Rhythms 8:3CrossRefGoogle Scholar
  28. Reiter RJ (1991) Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 79:C153–C158CrossRefGoogle Scholar
  29. Rutter J, Reick M, LC W et al (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293:510–514CrossRefGoogle Scholar
  30. Santidrian AF, Matsuno-Yagi A, Ritland M et al (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123:1068–1081CrossRefGoogle Scholar
  31. Santidrian AF, Leboeuf SE, Wold ED et al (2014) Nicotinamide phosphoribosyltransferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer. DNA Repair (Amst) 23:79–87CrossRefGoogle Scholar
  32. Shah PN, Mhatre MC, Kothari LS (1984) Effect of melatonin on mammary carcinogenesis in intact and pinealectomized rats in varying photoperiods. Cancer Res 44:3403–3407PubMedGoogle Scholar
  33. Smith J (2002) Human Sir2 and the ‘silencing’ of p53 activity. Trends Cell Biol 12:404–406CrossRefGoogle Scholar
  34. Stevens RG, Zhu Y (2015) Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem? Philos Trans R Soc Lond Ser B Biol Sci 370:20140120CrossRefGoogle Scholar
  35. Xiang N, Zhao R, Song G et al (2008) Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis 29:2175–2181CrossRefGoogle Scholar
  36. Yang T, Sauve AA (2006) NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. AAPS J 8:E632–E643CrossRefGoogle Scholar
  37. Zhang X, Zarbl H (2008) Chemopreventive doses of methylselenocysteine alter circadian rhythm in rat mammary tissue. Cancer Prev Res (Phila) 1:119–127CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Department of Environmental and Occupational Health, School of Public Health Environmental and Occupational Health Sciences InstituteRutgers, The State University of New JerseyPiscatawayUSA

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