Circadian rhythms and cancer

Abstract

The circadian clock is an endogenous time keeping system shared by most organisms. In mammals, a master pacemaker in the hypothalamus orchestrates temporal alignment of behavior and physiology by transmitting daily signals to multiple clocks in peripheral tissues. Disruption of this communication has a profound affect on human health and has been linked to diverse pathogenic conditions, including cancer. At the center of the molecular circadian machinery is a set of clock genes, generating rhythmic oscillations on a cellular level. In the past several years, research from different fields has revealed the complexity and ubiquitous nature of circadian regulation, uncovering intriguing associations between clock components and cellular pathways implicated in tumorigenesis. In this review, we discuss the emerging role of circadian genes in hematological and hormone-related malignancies. These new insights suggest that manipulating circadian biology as a way to fight cancer, as well as, other life threatening diseases is within the realm of possibility.

Figure 1

Connections between circadian cycles, C/EBPs and the NAD⁺-Sirt1 pathway may affect G-CSF induced granulopoiesis. The circadian oscillator is composed of transcriptional feedback loops (Red). Clock and Bmal1 drive expression of core clock genes Per, Cry and Rev-Erbα which in turn, inhibit Clock/Bmal1 activity. Throughout the body, these clock cycles are embedded into tissue-specific pathways to sustain local rhythmic physiologies. The Clock/NAD⁺-Sirt1 feedback loop (brown) couples circadian oscillations to metabolism. Diurnal cytokine patterns link circadian regulation to hematopoietic processes (orange). C/EBP transcription factors may form a feedback loop with the circadian clock (purple) as they regulate core clock genes and are themselves rhythmically expressed in some tissues. In myeloid cells, C/EBPs are part of a feedback loop (green) that regulates granulocyte colony stimulating factor (G-CSF) and G-CSF receptor (G-CSFR) in a NAD⁺-Sirt1 dependent manner, leading to induction of granulopoiesis.

Figure 2

Per couples the circadian cycle to the androgen response. Clock and Bmal1 activate the transcription of core clock genes (e.g., Per and Cry) as well as tissue specific rhythmic genes (e.g., AR). Per and Cry heterodimerize and inhibit the Clock/Bmal1 complex. Tissue specific transcription factors like AR, additionally regulate the expression of core clock genes. In turn, Per binds to AR and inhibits AR transcriptional activity. Metabolic and chromatin remodeling cycles further integrate into the circadian control of normal cellular function.