Potential Role of Circadian Clock in Cancer Evolution: Comparison
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Circadian rhythms, including sleep/wake cycles as well as hormonal, immune, metabolic, and cell proliferation rhythms, are fundamental biological processes driven by a cellular time-keeping system called the circadian clock. Disruptions in these rhythms due to genetic alterations or irregular lifestyles cause fundamental changes in physiology, from metabolism to cellular proliferation and differentiation, resulting in pathological consequences including cancer. Cancer cells are not uniform and static but exist as different subtypes with phenotypic and functional differences in the tumor microenvironment. At the top of the heterogeneous tumor cell hierarchy, cancer stem cells (CSCs), a self-renewing and multi-potent cancer cell type, are most responsible for tumor recurrence and metastasis, chemoresistance, and mortality. Phenotypically, CSCs are associated with the epithelial-mesenchymal transition (EMT), which confers cancer cells with increased motility and invasion ability that is characteristic of malignant and drug-resistant stem cells. Recently, emerging studies of different cancer types, such as glioblastoma, leukemia, prostate cancer, and breast cancer, suggest that the circadian clock plays an important role in the maintenance of CSC/EMT characteristics.

  • circadian clock
  • cancer stem cells
  • epithelial–mesenchymal transition

1. Introduction

Circadian clocks are cell-autonomous timing systems that generate roughly 24 h periodic rhythms and are conserved in nearly all life, from unicellular organisms to humans. These internal timing systems integrate with diverse environmental (e.g., light, temperature) and metabolic (e.g., food intake) stimuli to regulate a myriad of temporal biological activities, including sleep/wake, feeding times, energy metabolism, hormonal and immune functions, and cellular proliferation and differentiation [1]. Evolutionarily, these flexible clock systems are thought to help organisms survive better by increasing their ability to timely anticipate and adapt to the cyclic changes of light and food availability as well as predation risk [2,3][2][3]. At the unicellular level, as in the case of all prokaryotes that are classified into bacteria and archaea, the timely compartmentalization of biochemical and redox processes by the intrinsic circadian clock ensures the temporal fitness of cell physiology and functions across species [4]. In lower eukaryotic species, including yeast and fungi, biological timekeepers may help these single-celled organisms escape the DNA-damaging effects of ionizing radiation from sunlight as well as oxidative stress during cell division [5,6,7][5][6][7]. In higher, complex organisms, such as most vertebrate species, including humans, multi-stimuli responsive oscillators in neurons and fibroblasts are tightly coupled to form the brain and peripheral organ clock systems, which, in turn, constitute a body-wide circadian network with adaptive capacity for the environmental entrainment of rhythmic behaviors and physiology [8].
In contrast to the evolutionarily adaptive benefits of circadian rhythms, rhythm disruptions, primarily due to modern lifestyles lacking regular patterns of working, eating, and sleeping, have been recognized to increase the susceptibility of humans to the onset and development of cardio-metabolic and immune disorders as well as multiple types of cancers [9,10,11,12][9][10][11][12]. Furthermore, several studies of animal models possessing genetic mutations in clock genes or exposed to forced circadian desynchrony regimens have strengthened the causal relationship between circadian disturbances and pathological consequences [13,14,15,16][13][14][15][16]. In particular, genetic and environmental perturbations of circadian rhythms largely alter the expressions and activities of several tumor suppressors and oncogenes in both host and tumor tissues in favor of cancer incidence and progression [17,18][17][18]. These circadian disruptions also reprogram host metabolism and immune systems, facilitating an immunosuppressive tumor microenvironment and enabling tumor progression and metastasis of multiple cancer types [13,14,19][13][14][19].
One of the most formidable issues in cancer diagnosis and treatment is cancer cell heterogeneity and plasticity, the adaptive capacity of diverse cancer cell populations to survive upon tumor-environmental challenges [20]. Cancer cells in tumor tissues are not uniform, but consist of distinct types of cell subpopulations that can change their cellular morphology, physiology, and behavior in response to tumor-intrinsic and extrinsic changes (e.g., gene mutations, low nutrient or oxygen levels, immune surveillance, or toxic drug exposure) [20,21][20][21]. Among the different tumor cell populations, the cancer stem cell (CSC), a self-renewing cancer cell type with multi-differentiation potential, is highly responsible for tumor recurrence and metastasis, therapy resistance, and mortality [21]. The generation of tumor cells with stem cell properties has been closely linked to the epithelial–mesenchymal transition (EMT), a process that increases the migratory and invasive capacities of cancer cells, leading to drug-resistance and metastatic potential in CSC populations [22,23][22][23]. Accordingly, effective eradication of these deadly cell populations during chemotherapeutic intervention is becoming more important for improved therapeutic outcomes. Growing evidence suggests that the cellular heterogeneity observed in several cancer types is not just genetically determined but also arises from inherent cancer cell plasticity instructed by the tumor-extrinsic microenvironment [24,25,26,27,28][24][25][26][27][28].

2. The Molecular Clockwork and Circadian System

In all living organisms, the basic biological timing unit is the cell. In mammals, including humans, circadian rhythms are primarily driven by a cell-autonomous molecular feedback mechanism in which the circadian transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (BMAL1) and circadian locomotor output cycles kaput (CLOCK) cyclically activate the expressions of their own repressors, period (PER) and cryptochrome (CRY) [29]. The core oscillator is complemented by a second loop in which cycling expression of BMAL1 is maintained by the REV-ERBα/β repressor and RORα/β activator proteins [29] (Figure 1A). Besides the core regulatory loops, multiple levels of epigenetic, posttranscriptional, and posttranslational regulation involving various kinases, phosphatases, ubiquitin-proteasome pathway components, nuclear-cytoplasmic transporters, non-coding RNAs, and chromatin remodelers contribute to the molecular clockwork, thus coordinating temporal programs via multiple clock-output genes involved in cellular physiology and metabolism [30,31,32,33,34,35,36,37][30][31][32][33][34][35][36][37]. The core clock machinery is mobilized to reset cellular rhythms upon intrinsic and extrinsic stimuli involving multiple post-translational (e.g., phosphorylation, sumoylation) and metabolic (e.g., Ca2+, cAMP) signaling pathways [32,36,38,39][32][36][38][39]. Systemically, oscillators that respond to multiple stimuli in neurons and fibroblasts are tightly coupled to form the brain and peripheral organ clock systems, which, in turn, constitute a body-wide circadian network with adaptive synchronous capacity for environmental entrainment of rhythmic behaviors (e.g., sleep/wake and feed/fast cycles) and physiology (e.g., temperature, blood pressure, energy metabolism, immune functions, cellular proliferation and differentiation) [30]. In particular, the hypothalamic suprachiasmatic nucleus (SCN), a central circadian pacemaker in the brain, communicates retinal light input to peripheral clock systems, thus mediating periodic synchronization of internal body rhythms with external day and night cycles [40] (Figure 1B). Besides SCN-mediated photic entrainment, a growing number of studies report that non-SCN brain regions (e.g., substantia nigra [SN], nucleus accumbens [NA], arcuate nucleus [ARC], choroid plexus [CR]), and peripheral tissues (e.g., liver, kidney, muscle, and adipose) possess their own autonomous and muti-stimuli entrainable oscillators that influence not only circadian functions in the SCN and neighboring local clocks, but also whole body rhythms via neural, hormonal, and metabolic feedback mechanisms [11,41,42,43,44,45,46,47,48,49][11][41][42][43][44][45][46][47][48][49].
Figure 1. The core circadian timing systems in mammals. (A) Schematic of the molecular mechanisms of the circadian clock oscillator. At the molecular level, the circadian loop consists of a core loop and a stabilizing loop. In the core loop, the heterodimer BMAL1/CLOCK binds to the E box enhancer element (E) of the PER and CRY genes to initiate transcription. PER and CRY proteins accumulate before they heterodimerize and act as a transcriptional repressor. Expression of BMAL1, a core clock gene, is controlled by an ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. (B) The suprachiasmatic nucleus (SCN), a small region in the brain, represents the highest hierarchy of core clock functions. When light stimuli are transmitted to the SCN through the retinohypothalamic tract (RHT), the SCN acts as a central pacemaker to synchronize the circadian clocks present in peripheral organs and coordinate temporal physiology. However, non-photic external cues (e.g., temperature changes, food intake, metabolic stimuli, hormonal changes) can reset circadian rhythms in peripheral clock tissues, thereby influencing the rhythmic output of physiology and behaviors.

3. Circadian Disruption and Cancer Pathogenesis

Mirroring the interactive features of biological clock systems, studies in both human and animal models have suggested that daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift) and life schedules (e.g., jet lag, mistimed eating), cause physiological complications that increase the risk of cardiac, metabolic, neurological, and neoplastic diseases [9,10,11,12][9][10][11][12]. Globally, artificial light sources in modern society are a primary contributor to disrupted circadian rhythmicity. Eighty percent of the world’s population is now exposed to light during the night, and about 18–20% of workers in the USA and Europe are engaged in night or rotating shift work, which predisposes them to multiple rhythm disorders, particularly cancer [50]. Indeed, several epidemiological studies suggest that night shift work and chronic jet lag increase the risks of onset and development of the most common cancer types (i.e., breast, lung, prostate, colorectal, and skin cancers) [51]. Based on such accumulating evidence, the International Agency for Research on Cancer (IARC) classified “shift-work that involves circadian disruption” as potentially “carcinogenic to humans (Group 2A)” in 2007 [52] and again in 2019 [53]. Besides work-related disruptions, additional factors that alter circadian rhythms, such as abnormal lighting conditions [54], irregular eating habits [55], and traumatic stress [56], may also contribute to tumor pathogenesis and progression. For example, a recent population-based case–control study reported that mistimed eating patterns increased the risks of breast and prostate cancers [57]. Overall, these findings underscore the importance of maintaining normal circadian rhythms for the prevention and management of cancer.

4. The Circadian Clock and Cancer Cell Proliferation

The relevance of the circadian clock to cancer pathophysiology has mainly been attributed to the regulatory relationship between the circadian clock and cell proliferation. Accumulating studies have unraveled molecular connections between the circadian clock and cell cycle-regulating factors [58,59][58][59]. Indeed, most of the genes regulating critical steps in the phases of the cell cycle have been found to be controlled by the circadian clock. For instance, c-MYC and cyclin D1, which induce entry into the DNA synthesis (S) phase, as well as WEE1, which controls entry into the mitosis (M) phase, exhibit circadian cycles of expression in a CLOCK/BMAL1-dependent manner [17,58,60,61,62][17][58][60][61][62]. There are also other cell cycle regulators and checkpoint controllers (e.g., p21, p16/INK4a, p27, and p57), as well as cell cycle signaling pathway factors (e.g., mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and transforming growth factor (TGF)), that are regulated by the circadian clock to mediate daily cycles of cell proliferation [63]. Furthermore, the DNA damage response, DNA repair mechanisms, and apoptotic signaling pathways, which are closely associated with cell cycle checkpoints, are directly controlled by circadian clock components, such as CLOCK, PER1/2, and CRY1/2 in the core loop and RORA and NR1D1/2 in the stabilizing loop, of the molecular clockwork [64,65,66,67,68,69,70][64][65][66][67][68][69][70]. Notably, a growing number of studies have suggested direct roles of clock genes in tumor proliferation and growth. For example, genetic or epigenetic silencing of BMAL1 and/or CLOCK has been shown to increase tumor proliferation or growth rates in hematologic cancer [71], colon cancer [72], pancreatic cancer [73], tongue squamous cell carcinoma (TSCC) [74], breast cancer [75], lung adenocarcinoma [18], hepatocellular carcinoma (HCC) [76], nasopharyngeal carcinoma (NPC) [77], and glioblastoma multiforme (GBM) [78]. Conversely, overexpression of these clock activators suppresses the proliferative and malignant properties of tumor cells via cell cycle arrest and p53-dependent apoptosis [78,79][78][79]. In line with this, downregulation or upregulation of the BMAL1/CLOCK target genes PER1, PER2, and CRY1 promote or suppress tumor onset and proliferation, respectively, in Lewis lung carcinoma (LLC), mammary carcinoma [80], pancreatic cancer [81], lung carcinoma [18], leukemia [82[82][83],83], glioma [84], ovarian cancer [85], and oral squamous cell carcinoma [86,87][86][87]. At the molecular level, these studies suggest that the anti-cancer activity exerted by PER1/2 occurs via the inhibition of PI3K/AKT/mTOR-mediated glycolysis as well as cell cycle arrest and apoptosis induction [80,86,87][80][86][87]. In addition, recent studies from the Lamia group have reported that CRY1 and/or CRY2 promote the degradation of cMYC, early 2 factor (E2F) family members, and tousled like kinase 2 (TLK2) by recruiting these cell cycle-related oncogenic factors to the SCFFBXL3 ubiquitin-ligase complex [88]. Correlating with this, a recent large-scale systems analysis of 32 human cancer types has revealed that PERs and CRYs, along with several other clock genes, are downregulated in several types of cancers [89]. Taken together, these findings indicate that core clock components have tumor suppressor functions in most cancer types. However, most of these chrono-cancer studies have been based on bulk analyses of tumor cells grown in monolayer cultures or on tumor tissues grafted in mice, which are unable to recapitulate the spatiotemporal variations in phenotypes or the functions of distinct cancer cell populations in tumors under normal or abnormal circadian conditions [17].  

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