Clocking cancer: the circadian clock as a target in cancer therapy
The integration of circadian biology into cancer research is leading to the development of a novel therapeutic paradigm with unique potential to leverage the interplay between the circadian machinery and major cancer-related pathways.
The field of chronobiology has been around for many years and received much attention in 2017 when the Nobel Prize in Physiology or Medicine was awarded to Michael W. Young, Jeffrey C. Hall, and Michael Rosbash “for their discoveries of molecular mechanisms controlling the circadian rhythm”. Since then, much of the studies conducted in mammalian models have aimed to better understand how our circadian rhythms contribute to overall human physiology and, consequently, health and disease. There has been a myriad of studies that aim to understand how sleep and jet lag contribute to increase in mental illness, metabolic, heart, and inflammatory diseases, neurodegeneration, and cancer. Such research aims to understand how to better modulate modern human behavior to fit our body’s needs. For example, one such trend to emerge from such studies is time-restricted eating or intermittent fasting, which aims to improve overall metabolic health and control metabolic disease, such as diabetes and obesity. Given the broad role of circadian control in regulating gene expression in many tissues, not surprisingly it has been found that the circadian clock genes and machinery themselves can contribute to the pathogenesis of a number of different diseases. In the case of cancer, circadian components can either play an oncogenic or tumor suppressive role depending on the type of cancer and the downstream clock targets that are driving carcinogenesis.
Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are two principle clock proteins that form a heterodimer and bind to E-box of clock-controlled gene (CCG) promoters to regulate CCG transcription. At the core loop of the clock, repressors Cryptochrome1/2 (CRY1/2) and Period1/2 (PER1/2) form a heterodimer to inhibit BMAL1::CLOCK transcriptional activity. In the secondary loop of the clock, Retinoic Acid Receptor-Related Orphan Receptorα/β/γ (RORα/β/γ) or REV-ERBα/β, respectively, converge upon the ROR response element (RORE) motif of the BMAL1 promoter to either promote or inhibit transcription. Post-translational modifications that control protein localization and/or degradation help to fine tune the clock and contribute to cycling in CCG expression.
Given the ties between the clock and disease pathogenesis in general, a number of small molecules have been screened and developed to pharmacologically target BMAL1 transcription and/or BMAL1::CLOCK transcriptional activity. Molecules that have been studied specifically in the context of cancer include: REV-ERB agonists, REV-ERB antagonists, ROR agonists, CRY stabilizers, CRY inhibitors, Casein Kinase 1 (CK1) inhibitors, CK2 inhibitors, and Glycogen Synthase Kinase-3 Beta (GSK-3β) inhibitors. These clock compounds either interact with CRY1/2 or PER1/2 turnover mechanisms or they modulate RORα/β/γ or REV-ERBα/β activity in order to inhibit or promote clock driven transcription. They hold the potential to be applied either as single agents or in combination with each other or with current standard of care methods depending on what circadian machinery a specific tumor type relies on for oncogenic signaling or inhibition of tumor suppressive activities.
In our review, we discuss the mammalian clock mechanism; the disruption of circadian rhythms and the involvement of clock components in cancer pathogenesis; ties between clock proteins and other tumor suppressors or oncogenes in a variety of cancer types; studies investigating the use of small molecule modulators of the clock as novel cancer therapies; and our perspectives on the future of circadian biology as it pertains to cancer research and the clinic. Studies to date suggest that leveraging circadian machinery and major molecular cancer pathways will be a promising novel avenue to pursue, but further in depth studies are required to fully elucidate the efficacy of modulating circadian rhythms in anti-cancer treatments across numerous tumor types.
Circadian Clock Components and Cancer Hallmarks