Abstract
Circadian clocks are innate oscillators that drive daily rhythms in metabolism, physiology, and behavior. 24-h rhythms in gene expression, driven by core clock transcription factors, reflect the epigenetic state of the cell, which in turn is dictated by the metabolic environment. Cancer cells alter their metabolic state and gene expression and therefore are likely to tweak circadian clock function in their favor. Over the past decade, we have witnessed an extraordinary increase in systems-level studies that suggest intricate mechanistic links between the cellular metabolome and the circadian epigenome. In parallel, reprogramming of cellular clock function in cancers is increasingly evident and the role of clock genes in the development of hematological tumors, as well as their pathophysiological effects on tissues distal to the tumor, has been described. Furthermore, the interplay between components of the circadian clock, metabolic enzymes, and oncogenes is starting to be better understood, such as the close association between overexpression of the Myc oncogene and perturbation of circadian and metabolic rhythms, thus opening new avenues to treat cancers. This review article explores current knowledge on the circadian metabolome and the molecular pathways they control, with a focus on their involvement in the development of hematopoietic malignancies.
Highlights
Far from being an unidirectional regulatory event, circadian transcription that drives oscillations in small metabolites is in turn affected by the abundance of these small molecules
While homeostasis with the environment ensures a regular rhythm in metabolite levels, perturbations that arise from modern lifestyles have all been shown to alter rhythmic pathways
Many malignancies of hematological origin, which account for nearly 10% of clinical diagnoses of all cancers, display altered clock function and parallel widespread metabolic arrhythmia
Summary
Circadian clocks are ubiquitous timers that synchronize physiology, metabolism, and behavior with the solar day. A BMAL1:CLOCK transcription factor heterodimer drives the expression of the repressor complex component genes PER and CRY, which assemble into a ~1 MDa complex with other proteins to repress BMAL1:CLOCK function on chromatin [7,8,9] This negative feedback inhibits new PER and CRY synthesis. RORs activate transcription of BMAL1, whereas REVERBs represses it, effectively buffering BMAL1 levels and thereby stabilizing circadian transcription in individual cells [14] These pathways eventually impinge on regulation of rhythmic behavior and metabolism [15]. These cis-acting elements, the E-boxes and ROREs, together help to promote precisely phased circadian transcription of clock output genes throughout the genome. The past few years have expanded the output pathways beyond the coding genome to a large fraction of the non-coding genome as well as the metabolome [10, 13, 16]
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