Review

Clocks, cancer, and chronochemotherapy

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Science  01 Jan 2021:
Vol. 371, Issue 6524, eabb0738
DOI: 10.1126/science.abb0738

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Doubts in cancer-rhythms connections

Circadian clocks help to coordinate physiological processes with the daily cycles of light and dark and periods of feeding, activity, and rest. Being out of sync with such 24-hour cycles can have unhealthy effects. Sancar and Van Gelder review the available evidence regarding circadian disruption and predisposition to cancer and circadian variations in response to cancer chemotherapy. The literature can be difficult to interpret. For example, complete knockouts of clock genes are not the same as shift work. Overall, they find that the jury is still out on whether circadian disruption can promote cancer in general and if the timing of cancer treatment can be optimized. However, enough indications are present that further research is recommended.

Science, this issue p. 42

Structured Abstract

BACKGROUND

The core of the mammalian circadian clock mechanism is a time-delayed transcription-translation feedback loop (TTFL), which influences the transcription and expression of a large fraction of the transcriptome. Through this mechanism, the mammalian circadian clock modulates many physiological functions, including the timing of cell division and rates of metabolism in specific tissues. Circadian clock dysfunction is associated with several human disease states, including jet lag and sleep phase disorders, and it likely contributes significantly to the development of metabolic syndrome. With respect to cancer, animal studies have suggested that specific carcinogenic mechanisms, such as ultraviolet radiation for skin cancer, have a strong circadian rhythm. Epidemiologic studies have yielded conflicting results as to whether circadian clock disruption by night or shift work is carcinogenic. In animal studies, tumors grafted into animals with disrupted rhythms grow more rapidly than those grafted into control animals. Studies of mice genetically lacking specific components of the circadian clock show increased rates of tumorigenesis for certain clock genes and certain tumors but show reduced rates for other clock genes. Similarly, the response to chemotherapy may also vary with time of day, which has led to enthusiasm for chronochemotherapy as a means to improve the therapeutic efficacy of cancer treatment while limiting toxicity. However, clinical trials of chronochemotherapy have generally not shown improved efficacy and have even shown worse outcomes in subsets of patients compared with conventionally timed therapies.

ADVANCES

Polymorphisms in circadian clock genes including Npas2 and Clock have been identified in genome-wide association studies as relatively weak but significant modifiers of breast cancer incidence, and core circadian clock gene expression is frequently dysregulated in human tumors. However, it is not possible to generalize that loss of the clock leads to increased cancer incidence, as some clockless animals actually show resistance to specific cancer pathways (e.g., Cryptochrome-less mice are resistant to p53 mutation–induced tumors). In other cases, different clock gene mutations result in opposite phenotypes with respect to carcinogenesis for the same tumor type. Perhaps the best-studied mechanistic interaction between circadian clock and carcinogenesis involves studies of the circadian rhythms of nucleotide excision DNA repair. Although basal excision repair has a circadian rhythm with a specific maximal phase, the rhythm of an individual gene’s repair is dependent on the phase of that gene’s transcriptional rhythm; there is no single phase at which DNA is generally more or less easily repaired. Other notable advances in the field include the demonstration of direct mechanistic linkage of c-MYC expression to circadian clock control and the demonstration that oncogenes c-Myc, p53, and Ras all affect the circadian core TTFL, consistent with the finding that the circadian clock of tumors is frequently dysregulated.

OUTLOOK

Tumorigenesis is clearly affected by circadian mechanisms, but the hypothesis that circadian clock genes are general tumor suppressors is not supported. Rather, specific tumors and their underlying mechanisms are differentially affected by the function of specific clock genes. Conversely, specific oncogenes may cause dysregulation of the circadian clock in tumors; the pathogenic significance of the dysregulated clock in tumors is not fully understood. The example of circadian control of DNA nucleotide excision repair illuminates the challenges in exploiting the interaction between clocks and cancer clinically, as the phase of circadian susceptibility to DNA damage varies for each gene on the basis of its underlying transcriptional rhythm. Although the concept of chronochemotherapy is attractive, the complexities of clock-cancer interactions make prediction of the effects of timed drug administration challenging. Mistiming of chemotherapeutic agents has the potential to be harmful. As chemotherapeutic agents increase in specificity, the circadian effects of administration may be better understood and optimized by understanding the specific interactions between the circadian clock mechanism and therapeutic targets.

Mammalian circadian clock controls transcription and DNA repair.

(Left) The mammalian circadian clock mechanism is a time-delayed TTFL. BMAL1-CLOCK constitute the positive arm and cryptochrome (CRY1 and CRY2)–period (PER1 and PER2) constitute the repressive arm; the primary feedback loop is consolidated by a secondary loop made up of REV-ERBα inhibitor and RORα activator. In a given tissue, ~10% of the genes are expressed with significant circadian (near–24 hour) periodicity. (Right) Effect of the clock on transcription and nucleotide excision repair in mice is shown in two heatmaps, where the green (transcription) and yellow (repair) represent the intensity of the signal. The left-side expression heatmap shows 854 clock-controlled transcripts in the livers of mice kept in the dark for 44 hours [adapted from B. H. Miller et al., Proc. Natl. Acad. Sci. U.S.A. 104, 3342 (2007), Copyright (2007) National Academy of Sciences]. Each of these genes is expressed maximally at a specific time of day. The right-side repair heatmap shows 1661 genes from the kidneys of mice kept under a 12-hour light–12-hour dark condition treated with the chemotherapeutic cisplatin [adapted from Y. Yang et al., Proc. Natl. Acad Sci. U.S.A. 115, E4777 (2018), Copyright (2018) National Academy of Sciences]. Damage is quantified for both transcribed strands (TS) and nontranscribed strands (NTS). The NTS shows a monophasic rhythm for all genes with a peak in early evening. For the TS, each gene shows a specific maximum for repair during the cycle corresponding to its peak phase of transcription. The complexity of individual gene repair timing creates substantial challenges for optimizing circadian timing of chemotherapy administration.

Abstract

The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.

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