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Circadian Rhythm in Carcinogenesis and Chemoprevention

Posted at 3:41 pm July 26, 2011, in Research Highlights

Dr. Helmut Zarbl, EOHSI faculty member and CEED Director

Essentially all organisms on the planet have a circadian rhythm, or biological clock, that controls a wide variety of basic physiological and cellular functions that vary in a cyclical pattern throughout the day. Biological processes under circadian control include everything from sleep/wake cycles to DNA repair. At the cellular level, circadian rhythm is controlled by an elegant molecular clock or oscillator that runs with a periodicity of approximately 24 hours. To coordinate the circadian activities of the trillions of cells that make up the body, these individual peripheral clocks must be synchronized by a central pacemaker, much in the way that all timepieces on the planet are synchronized to Greenwich Mean Time (Coordinated Universal Time). In higher organisms, circadian clocks are synchronized to the to the light/dark cycle of the planet by the amount of light that enters the eye and hits specialized photoreceptors (melanospin-containing ganglion cells) in the retina that send electrical signals to the Suprachiasmatic Nucleus (SCN). The latter innervates the pineal gland in the brain, where in controls the production and release of the hormone melatonin into the circulation. Melatonin then binds to specific receptors on the surface of peripheral cells and stimulates the expression of circadian and circadian controlled genes in a dose dependent manner. In this way the amount of blue light entering the eye is able to synchronize the periodicity of molecular oscillators in all cells.

Studies in the our laboratory showed that exposure to carcinogenic doses of chemical carcinogens can ablate normal circadian rhythm in the target organ, suggesting a direct link between carcinogen exposure, disruption of circadian rhythm, and carcinogenesis. Consistent with this hypothesis, studies in the laboratory showed that a dietary supplement of methylselenocysteine (MSC) not only reduced the incidence of mammary tumors in rats by 70%, but also reset the expression of circadian and circadian genes. Further studies showed that carcinogen ablated while MSC restored and enhanced the rhythmic expression of the cellular receptors for melatonin and estrogen, as well as DNA repair genes, providing a mechanistic link between loss of circadian rhythm and carcinogenesis. However neither carcinogen exposure nor dietary MSC altered the central pacemaker or the cyclical expression of serum melatonin.

More recent studies have investigated the molecular mechanisms by which dietary MSC is able to reset circadian gene expression disrupted by carcinogen exposure. Previous studies showed that the clock gene, a transcription factor that plays a major role in the regulation of circadian genes, also has histone acetyltransferase activity. Acetylation of histones leads to a more open chromation configuration, which facilitate the binding of transcriptional complexes to increase gene expression. By contrast Sirtuin 1 (Sirt1), which encodes a histone deacetylase, removes these histone mofications to leading to a reduction in gene expressions. The relative levels of these enzyme activities modifications fluctuate during a 24 hours determine the cyclical pattern of circadian gene expression. Studies our lab studies have demonstrated that carcinogen exposure ablates, while MSC restores the rhythmic acetylation of histone proteins within the promoter regions of circadian and circadian controlled genes. Preliminary results suggest that this involves alterations carcinogen- and MSC-induced changes in the cellular ratio of NAD/NADH, a modulator of Sirt1 histone deacetylase activity. Elucidating the exact epigenetic mechanisms of circadian regulation could lead to development of novel strategies to prevent the disruption of circadian rhythm by chemical exposures.

Disruption of circadian rhythm has significant physiological effects, that are familiar to anyone who has ever experienced sleep deprivation, jet-lag or worked the night shift. Moreover, epidemiological studies have repeatedly shown that chronic disruption of circadian rhythm by shift work (exposure to light at night) or jet-lag are associated with chronic illnesses, including a significantly increased risk of developing breast and prostate cancers. The findings that dietary MSC can restore circadian rhythm in mammary cells independent of serum melatonin are the basis for an ongoing intervention trial. The goal is to determine if MSC can restore peripheral clocks in shift workers. If so these finding would be the basis for a prospective trial to determine if MSC can also reduce the risk of breast and prostate cancers in those who serve the community by working at night.

Reference: Zhang X. and Zarbl H. (2008). Chemopreventive doses of methylselenocysteine alter circadian rhythm in rat mammary tissue. Cancer Prev Res (Phila) 1(2): 119-27. DOI:10.1158/1940-6207.capr-08-0036. PMCID:2519612.