Metabolic rivalry: circadian homeostasis and tumorigenesis

Abstract

Circadian rhythms govern a large array of physiological and metabolic functions. Perturbations of the daily cycle have been linked to elevated risk of developing cancer as well as poor prognosis in patients with cancer. Also, expression of core clock genes or proteins is remarkably attenuated particularly in tumours of a higher stage or that are more aggressive, possibly linking the circadian clock to cellular differentiation. Emerging evidence indicates that metabolic control by the circadian clock underpins specific hallmarks of cancer metabolism. Indeed, to support cell proliferation and biomass production, the clock may direct metabolic processes of cancer cells in concert with non-clock transcription factors to control how nutrients and metabolites are utilized in a time-specific manner. We hypothesize that the metabolic switch between differentiation or stemness of cancer may be coupled to the molecular clockwork. Moreover, circadian rhythms of host organisms appear to dictate tumour growth and proliferation. This Review outlines recent discoveries of the interplay between circadian rhythms, proliferative metabolism and cancer, highlighting potential opportunities in the development of future therapeutic strategies.

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Fig. 1: Organization of the circadian clock network.
Fig. 2: Molecular architecture of the circadian clock.
Fig. 3: Tumour-autonomous circadian clock.
Fig. 4: Regulation of proliferative metabolism by clock and non-clock TFs.
Fig. 5: Temporal communication between the circadian rhythm of host organisms and cancer-autonomous clocks.

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Acknowledgements

The authors thank S. Masri for insight and advice. They thank all members of the Sassone-Corsi laboratory for discussions and support. K.K. was supported by a JSPS fellowship. The authors’ research is supported by the National Institutes of Health (NIH), a Novo Nordisk Challenge Grant and INSERM (France).

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P.S.-C. and K.K. researched data for the article, made substantial contributions to discussion of content and wrote, reviewed and edited the manuscript.

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Correspondence to Kenichiro Kinouchi or Paolo Sassone-Corsi.

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Dedication

Kenichiro Kinouchi dedicates this article to the memory of Paolo Sassone-Corsi, for his outstanding contributions and scientific advancements in the fields of circadian rhythms, epigenetics and metabolism, and expresses the deepest appreciation for his mentorship and generosity.

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Nature Reviews Cancer thanks J. Borniger, C. Dang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Diurnal feeding–fasting behaviour

The daily behaviour of feeding and fasting under day–night cycles.

Hypothalamic suprachiasmatic nucleus

A group of oscillator neurons that govern circadian rhythms of physiology and behaviour.

Autonomic nervous system

A network of peripheral nerves that govern fundamental organ functions, often unconsciously.

Sympathetic nervous system

A stimulatory branch of the autonomic nervous system that is activated in fight or flight response.

Lipogenesis

A reductive metabolic process of synthesizing lipids by gaining electrons frequently activated in proliferating cells.

Lysosomal dispersion

The peripheral redistribution of normally perinuclear lysosomes.

Cancer/testis antigen

A class of antigenic proteins present on some human cancers but not on adult normal tissues except for testes.

Polysynaptic pathways

Neural pathways comprising multiple neural connections in which signals are transmitted.

Ventromedial hypothalamus

A specialized hypothalamic nucleus that controls appetite and thermogenesis.

Ketogenesis

A metabolic process that produces ketone bodies from fatty acids or amino acids.

Hypocretin/orexin neurons

A group of neurons in the lateral hypothalamus that regulate wakefulness and appetite.

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Kinouchi, K., Sassone-Corsi, P. Metabolic rivalry: circadian homeostasis and tumorigenesis. Nat Rev Cancer 20, 645–661 (2020). https://doi.org/10.1038/s41568-020-0291-9

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