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Metabolism and cancer: the circadian clock connection

Key Points

  • Circadian rhythms are endogenously generated rhythms that occur with a periodicity of around 24 hours.

  • There is an intimate link between the disruption of circadian rhythms and cancer. The circadian clock regulates key aspects of cell growth and survival, including the cell cycle, DNA damage responses, cellular senescence and metabolism.

  • Several cell cycle genes, such as WEE1, MYC and cyclin D1, are regulated by the circadian clock. This could be one way by which the circadian clock gates cell division.

  • Key clock proteins, such as PER1 and timeless, interact with proteins involved in the DNA damage responses. DNA damage itself can reset the clock.

  • Cellular metabolism is altered in cancer. Several key metabolic genes are under circadian regulation. Recent findings that SIRT1, a key regulator of metabolism, is an integral part of the clock machinery suggest that the circadian clock can regulate cellular metabolism in multiple ways.

  • The transcriptional negative feedback loop that regulates the circadian clock is interlocked with an enzymatic feedback loop in which SIRT1 regulates the levels of its own cofactor, NAD+.

Abstract

Circadian rhythms govern a remarkable variety of metabolic and physiological functions. Accumulating epidemiological and genetic evidence indicates that the disruption of circadian rhythms might be directly linked to cancer. Intriguingly, several molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of the cell cycle, and alterations in clock function could lead to aberrant cellular proliferation. In addition, connections between the circadian clock and cellular metabolism have been identified that are regulated by chromatin remodelling. This suggests that abnormal metabolism in cancer could also be a consequence of a disrupted circadian clock. Therefore, a comprehensive understanding of the molecular links that connect the circadian clock to the cell cycle and metabolism could provide therapeutic benefit against certain human neoplasias.

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Figure 1: The circadian feedback loop.
Figure 2: Regulation of the cell cycle and DNA damage response by the circadian clock.
Figure 3: Circadian regulation of the NAD+ salvage pathway.
Figure 4: Regulation of metabolism and the cell cycle by CLOCK–BMAL1 and SIRT1.

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Acknowledgements

We wish to apologize to all colleagues whose work, because of lack of space, could not be cited. We thank all the members of the Sassone-Corsi laboratory for helpful discussions. S.S. is supported by a postdoctoral fellowship from the American Heart Association, Western States Affiliates, USA. Work in our laboratory is supported by the National Institute of Health, USA, and the Institut de la Sante et de la Recherche Medicale, France.

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Glossary

Zeitgeber

A German word that literally means 'time giver', it refers to external cues that entrain the endogenous clock.

Melatonin

A hormone, primarily synthesized by the pineal gland, which has highest circulating levels at night.

E-box

A stretch of DNA with the sequence CACGTG, which is the most common motif in the mammalian genome.

Ultradian rhythms

Rhythms with a periodicity of less than 24 hours that are repeated several times in a circadian cycle. For example, heart rate and yeast metabolic rhythms.

Gluconeogenesis

The synthesis of glucose from non-carbohydrate sources (such as lactate and amino acids).

Nucleotide excision repair

A DNA repair process in which a short single-stranded region encompassing a DNA mutation is replaced. Defects in NER can lead to diseases such as Xeroderma pigmentosum.

Metabolic syndrome

A collection of risk factors, including high blood sugar levels, high blood pressure, large waistline, high blood triglyceride levels and low HDL blood cholesterol, which increases the risk for type 2 diabetes and cardiovascular diseases.

Hyperglycaemia

A condition in which blood glucose levels are high. It is generally a consequence either of low levels of insulin or insulin resistance.

Dyslipidemia

A risk factor for cardiovascular disease that refers to higher levels of triglycerides and low-density lipoprotein cholesterol but lower levels of HDL cholesterol in blood.

Hepatic steatosis

A condition, also known as fatty liver, in which large droplets of triglycerides accumulate in liver cells. It is commonly associated with alcoholism and obesity.

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Sahar, S., Sassone-Corsi, P. Metabolism and cancer: the circadian clock connection. Nat Rev Cancer 9, 886–896 (2009). https://doi.org/10.1038/nrc2747

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