Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.

Introduction

The human body operates on a finely tuned schedule governed by a unique biological clock, known as the circadian rhythm. This internal clock, regulated by specific genes, orchestrates a central clock in the brain that responds to environmental cues and synchronizes subordinate clocks in peripheral tissues through mechanisms tied to the day-night cycle. However, in our modern society, disruptions to this circadian rhythm, referred to as circadian rhythm dysregulation (CRD), have become increasingly common. This dysregulation poses significant threats to overall well-being, leading to adverse health outcomes, including metabolic, immune, and proliferative diseases [ 1 , 2 ]. A robust body of epidemiological and laboratory evidence has established a link between the biological clock and cancer [ 3 ], but the precise molecular mechanism underlying this association has yet to be comprehensively explained.

Findings from several research endeavors suggest that disruptions to the biological circadian rhythm, resulting from night shift work and exposure to light, have a close relationship with hormone-dependent cancers [ 4 - 6 ]. Early studies have shown that the biological clock can influence regulatory processes crucial to cancer development by coupling transcription and metabolism, thereby regulating cell differentiation and proliferation [ 1 , 3 , 7 ].

Core clock and non-clock transcription factors (TF) regulate proliferative metabolism and systematic communication between tumor and host cells in a coordinated manner [ 8 ]. Emerging evidence suggests that the biological clock controls metabolism and is a special feature of cancer metabolism [ 9 ]. The disturbance of circadian rhythm leads to disordered chromatin remodeling [ 2 , 10 ], which indicates that abnormal metabolism in cancer may also be the result of a biological clock disorder.

In experimental models and cancer patients, circadian rhythms substantially augment anticancer drug resistance [ 11 , 12 ]. An enhancement in efficacy was observed when drugs were administered during the optimal time periods, when the treatment is most effective and well-tolerated by patients. Conversely, when anticancer drugs are administered during the peak of their toxicity, the host's circadian clock is disturbed [ 13 ], chiefly because of the inherent dysregulation of the circadian rhythm in tumor cells, while healthy tissue rhythms remain intact. The immune system adapts to circadian rhythms, and both dendritic cells and lymphocytes are required to respond to these rhythms for proper cellular migration [ 14 ]. The absence of circadian rhythm implies the absence of peak immune activity [ 14 , 15 ]. Given this intricate relationship between the circadian rhythm and disease processes, the concept of chronotherapy has emerged as a promising strategy in optimizing treatment outcomes [ 16 - 18 ]. Chronotherapy involves the timing of medication administration to align with the body's biological rhythms, thereby enhancing drug efficacy and minimizing toxicity [ 19 ]. This approach has shown potential in cancer therapy, where the timing of drug delivery can significantly influence the therapeutic index [ 20 ]. By aligning treatment with the body's circadian rhythms, chronotherapy aims to maximize the effectiveness of drugs while reducing adverse effects, providing a novel avenue for improving patient outcomes. Our present focus delves into the interplay between CRD and tumorigenesis, tumor metabolism, and immune response, while underscoring the potential use of circadian rhythm in tumor therapy.

Circadian rhythm

The biological clock is a physiological rhythm system that regulates various behavioral activities and physiological functions within the living body via a self-regulating function and synchronization mechanism. The clock system that controls circadian rhythm in mammals is referred to as the circadian biological clock, which is primarily composed of central biological clock system and peripheral biological clock system [ 21 ]. The peripheral clock effectively oversees a multitude of molecular and cellular processes through various levels of regulation [ 22 ]. It is notable that a significant proportion of the genome is under the control of this clock, with over half of the protein-coding genes exhibiting varying diurnal oscillations within the tissue [ 23 ]. Furthermore, the regulation of the circadian rhythm of cellular activity extends beyond transcription and involves the rhythmic modulation of critical post-transcriptional processes such as RNA splicing, protein translation, and post-translation processing [ 24 ]. At the molecular level, circadian rhythms are the result of autonomous rhythms generated by oscillating clock genes [ 25 ]. The circadian rhythm system is a crucial regulatory system governing both bodily health and metabolism. It plays a vital role in regulating fundamental functions, including but not limited to gene expression, hormone release, energy consumption, cell growth, secretion, and metabolism [ 26 , 27 ]. Over the years, numerous studies have indicated a significant correlation between metabolic homeostasis and the regular biological clock [ 28 , 29 ]. Circadian rhythm participates in the metabolism of nutrients such as sugar and fat and in the metabolic regulation of various systems of the body [ 30 - 32 ]. Given that clock genes exhibit significant involvement in the regulation of neuroendocrine, immune, and cell cycle processes, with a notable impact on the cellular proliferation cycle and apoptosis. This close association with tumorigenesis and tumor metabolism further emphasizes its critical role in the maintenance of cellular homeostasis [ 33 - 36 ].

Molecular circuit of circadian rhythm

During the 1970s, Benzer and Konopka reported the isolation of one single-gene mutant in Drosophila that dramatically altered circadian rhythms in activity. In-depth research was conducted, the gene was designated as Period ( Per ) [ 37 ]. The protein encoded by Per functions as an inhibitor of its own transcription, leading to the emergence of rhythm [ 38 ]. Subsequently, the scientific community identified the Circadian motorcycle output kaput (Clock) gene, which is induced by Per and plays a significant role in mammalian organisms. This discovery highlights the role of activators in driving the expression of repressive genes, thereby creating a negative feedback loop that is conserved from Drosophila to humans [ 39 ]. The core clock mechanism consists of a self-regulatory network consisting of transcription-translation feedback loops (TTFL) incorporating both positive and negative feedback [ 39 ]. In terms of transcription, the circadian clock is facilitated by positive regulators within the loop. Basic helix-loop-helix heterodimer transcription factors (CLOCK/BMAL1 or BMAL1/NPAS2) are responsible for regulating the expression of pivotal circadian genes, including cryptochrome ( Cry1 and Cry2 ) and period ( Per1 , Per2 and Per3 ) genes, which function as negative regulators of the circadian circuitry [ 40 - 42 ]. Cry and Per forms a transcriptional repressor complex in the nucleus to inhibit CLOCK/BMAL1 activity, thus creating a negative feedback loop to control the clock. BMAL1 (brain and muscle ARNT-like protein 1) is also rhythmically controlled through its own transcriptional targets. Feedback timing is regulated through post-transcriptional modifications (e.g., splicing and translation), particularly post-translational modifications.

A prevalent regulatory pattern involves cyclic phosphorylation and degradation of biological clock constituents. These events are typically executed via the ubiquitin-proteasome system. The fundamental signaling pathway is fortified by the stimulation of REV-ERbα and ROR (Retinoid-related orphan receptor) α by CLOCK-BMAL1, which is integrated into additional transcriptional feedback mechanisms. Other transcription factors, such as USF1 and Dec1-Dec2, exert a feedback regulation over CLOCK activity [ 37 , 41 ] ( Fig. 1 ). RORs act as positive regulators by activating the transcription of BMAL1, while REVERBs function as negative regulators by repressing BMAL1 transcription [ 43 ]. This antagonistic interaction helps to establish and maintain the robustness of circadian rhythms. For example, RORα promotes BMAL1 expression, enhancing the transcription of clock-controlled genes [ 44 ], whereas REVERBα inhibits BMAL1 expression, thus dampening the circadian oscillations when needed [ 45 ]. The significance of the major clock regulators highlights the pivotal role of CLOCK/BMAL1 in modulating the expression of roughly 10% of clock-controlled genes that govern various molecular, biochemical, and physiological activities. Furthermore, protein stability is regulated by post-translational modifications of Cry and Per , whereas self-regulatory clock feedback loops can be influenced by repressors that control Cry or Per . These overlapping mechanisms confer daily rhythmicity in cellular, metabolic, and physiological functions to maintain homeostasis. Recent studies have shown that alterations in clock regulators are associated with cancer phenotypes [ 46 - 50 ].

CRD and tumorigenesis

The proliferation rhythm of tumor cells follows a different cycle pattern than that of normal tissue [ 51 - 54 ]. One of the characteristics of malignant tumors is the uncontrolled and disordered proliferation of cells, which is necessarily reflected in the disruption of the temporal dimension. Circadian clock genes are closely associated with tumorigenesis because they are closely related to neuroendocrine, immune, and cell cycle regulation, particularly affecting cell proliferation and apoptosis [ 55 , 56 ]. Research conducted in clinical settings has provided substantial evidence indicating that the disruption of homeostasis within circadian rhythms could potentially serve as an autonomous contributing factor to the development of cancer in humans [ 57 - 76 ] ( Table 1 ). Filipski et al. [ 34 ] designed a two-stage carcinogenic model in which mice were inoculated with implants of Glasgow osteosarcoma or pancreatic adenocarcinoma tumors at varying day and nighttime points. It was established that distinct time points showed significant variations in the tumor formation rate, number, and volume of tumor foci. This suggests that the disruption of the circadian rhythm in mice is related to the accelerated growth of two types of malignant tumors, indicating that the host biological clock may play an important role in the endogenous control of tumor progression.

The dysregulation of Clock genes in tumorigenesis

Clock genes play a crucial role in regulating the expression of proto-oncogenes, tumor suppressor genes, and transcription factors, thereby influencing tumorigenesis, development, and inhibition. Mutations in clock genes can lead to the upregulation of cell cycle suppressor genes and reduce the response of mutant cells to mitotic signals, significantly inhibiting cell growth and proliferation [ 81 , 118 - 120 , 121 ]. Decreased expression of clock genes results in heightened expression of the proto-oncogene c-MYC, which drives the uptake of glutamine and arginine. The upregulation of c-MYC promotes anabolic processes, increases cellular proliferation, and alters cellular metabolism, contributing to tumorigenesis [ 122 - 124 ].

Epigenetic inactivation of Bmal1 plays a key role in the development of hematological malignancies, such as non-Hodgkin's lymphoma and acute lymphoblastic leukemia. Specifically, Bmal1 inactivation occurs through hypermethylation of the cytosine-phosphate-guanine (CpG) island promoter, leading to disruption of the circadian rhythm of specific target genes, including c-MYC , catalase , and p300 , by interfering with the biological clock [ 110 ]. Inhibition of lung cancer metastasis and progression is elicited by Per2 and Bmal1 [ 125 ]. Methylation at the CpG site of hPer3 was observed in patients with chronic myeloid leukemia [ 116 ].

The promotion of cancer cell growth in vitro and the enhancement of time-dependent tumor growth in vivo occur exclusively during specific periods of the day, as a result of the downregulation of either Per1 or Per2 [ 126 ]. Both Per1 and Per2 can inhibit the occurrence of breast cancer by promoting apoptosis in vivo and reduce the risk of tumorigenesis by indirectly inhibiting c-MYC transcription [ 127 - 132 ]. The tumor inhibitory function of Per1 is evidenced by its ability to significantly impede the proliferation and growth of breast cancer cells, as demonstrated through a distinct diurnal expression pattern [ 91 , 133 ]. Per1 mediates tumor necrosis factor-α (TNF-α) to inhibit the proliferation of human pancreatic cancer cells (MIA PaCa-2) [ 134 , 135 ]. In a study of sporadic and familial primary breast cancer, Winter et al. [ 78 ] found that the expression of Per1 and Per2 in tumor tissues was significantly lower than that in normal breast tissues, especially the expression of Per1 in familial primary breast cancer, which was significantly lower than that in sporadic breast cancer specimens, indicating that the disorder of clock gene expression may be an important factor in the pathogenesis of familial breast cancer [ 77 ]. Zhao et al.’s [ 136 ] clinical study on 246 gastric cancer patients aged from 23 to 79 years old revealed a significant correlation between the expression of Per1 and Per2 and pathological stage. Notably, higher pathological stages were associated with lower expressions of Per1 and Per2 . Moreover, patients with low expressions of Per1 and Per2 had significantly shorter survival times than those with high expressions. Emerging evidence suggests that circadian genes may impact tumorigenesis through mechanisms beyond their traditional roles in regulating the molecular clock [ 137 , 138 ]. While circadian rhythms orchestrate various physiological processes, circadian genes such as Per1 and Per2 have been implicated in cell cycle regulation, DNA damage response, and apoptosis, which are critical in cancer development and progression [ 138 ]. Several studies have demonstrated that Per1 and Per2 can have distinct effects on tumorigenesis. For instance, Per1 has been shown to enhance DNA damage repair and apoptosis, thereby exerting tumor suppressive effects [ 139 ]. Conversely, Per2 mutations are associated with an increased risk of certain cancers, suggesting a complex role in tumorigenesis that might be context-dependent [ 140 ].

The genetic variation in functional polymorphisms of the circadian genes Cry2 and Ala394Thr in Neuronal PAS domain protein 2 (NPAS2) increases genetic susceptibility to non-Hodgkin's lymphoma [ 97 , 111 ]. Cry2 can promote ubiquitination and degradation of c-MYC , whereas deletion of Cry2 leads to enhancement of MYC -driven lymphoma in mice [ 141 ]. High expression of Clock , Per , and Cry is associated with longer metastasis-free survival, and loss of co-expression of Per3 and Cry2 is associated with increased metastatic risk of breast cancer [ 142 ]. The development of endometrial carcinoma may be linked to disruptions in the biological clock resulting from CpG methylation of the promoter regions of Per1 , Per2 , or Cry1 [ 108 ]. The relationship between clinicopathological parameters and the expression levels of Cry1 and Bmal1 core clock genes in epithelial ovarian cancer has been established. The independent prognostic factor of low expression of these genes has been identified, alongside staging and tissue subtypes [ 104 ]. Yang et al. [ 143 ] found that in 30 HCC samples, the mRNA levels of Per1 , Per2 , Per3 , and Cry2 were notably lower compared to the para-tumor tissues. Conversely, no significant changes were observed in the expression of CLOCK-BMAL1, Cry1 , and CK1ε/δ. These findings indicate a lower presence of Per1 , Per2 , Per3 and Cry2 in HCC samples. This trend of decreased gene expression was also observed in colorectal and pancreatic cancer. In animal studies, chronic jet lag in mice increased their susceptibility to various cancers. Additionally, mice with mutations in clock genes were found to have a heightened risk of carcinogenesis. These animal model findings underscore the potential impact of circadian disruption on cancer development, paralleling the gene expression trends observed in human cancers [ 124 , 113 , 144 ].

A large-scale case-control study conducted within the general population yielded compelling evidence linking genetic variability in genes related to circadian rhythm with the incidence of prostate cancer [ 97 ]. Melatonin demonstrates upregulation of mRNA levels of Clock , and Per2 , and downregulation of Bmal1 mRNA, thereby suggesting a protective effect on rhythm loss during tumor progression [ 81 , 145 , 93 ]. The fundamental mechanism that propels the process of mesothelioma is the marked imbroglio of the clock gene [ 146 ].

Correlation between oncogenes, tumor suppressors, and CRD( Fig. 2 )

3.2.1 MYC

The MYC transcription factor is widely utilized for regulating cellular differentiation and proliferation by implementing a range of mechanisms, including the transcriptional amplification of target genes [ 147 ]. As previously discussed, the expression of biological clock genes has been observed to impact MYC , just as the regulation of C- MYC occurs through F-box and WD repeat domain containing protein 7 (FBXW7). The interplay between CRY2 and F-box and leucine-rich repeat protein 3 (FBXL3) stimulates the process of ubiquitination and consequent degradation of C-MYC [ 141 , 148 ]. According to current reports, the circadian rhythm inhibitor CRY2 has been found to facilitate degradation of the oncogenic transcription factor MYC through E3 ligase complex FBXL3. Conversely, research has demonstrated that the removal of CRY2 results in an exacerbation of MYC -mediated lymphoma development in murine models [ 141 ]. It is of note that DNA damage not only intensified the interplay between FBXL3 and CRY2 [ 149 ], but a recent investigation discovered that FBXL3 was the singular F-box substrate to elicit a response to DNA damage among the four, manifesting a notable augmentation in the recruitment of CUL1 [ 150 ]. In addition, CLOCK/BMAL1 is directly bound to the promoter region of C-MYC , resulting in its downregulation. Conversely, MYC was found to hinder CLOCK/BMAL1-dependent transactivation of PER1 expression [ 151 ]. These conclusions are bolstered by the adverse relationship between BMAL1 expression and MYC in a sample of 102 human lymphomas [ 152 ]. Furthermore, Per2 mutant mice ( Per2 m/m ) are susceptible to lymphoma and exhibit upregulation of C-MYC expression and its target gene CCND1 [ 153 ]. Taken together, these data suggest an opposing relationship between MYC and the circadian transcriptional axis that controls cell survival and proliferation pathways.

RAS

The RAS gene family ( K-RAS , H-RAS and N-RAS ) is encoded by different genes located on each of the three chromosomes [ 154 ]. RAS proteins are significant constituents of signaling pathways involved in cellular growth and proliferation. In certain cases, mutations in RAS can result in anomalous cell proliferation, eventually leading to tumorigenesis [ 155 , 156 ] Mutations in RAS can accelerate changes in cellular metabolism and influence circadian rhythms. Recent research has uncovered that while wild-type RAS interacts with circadian rhythms, mutant RAS may significantly impact these rhythms [ 157 , 158 ]. The study conducted unveils that human keratin-forming cells, which were H-RAS transformed, manifested a lack of gene expression for Per2 and Bmal1 . Conversely, the expression of Cry1 and Clock was upregulated within the synchronized cells [ 159 ]. The introduction of H-RAS or K-RAS results in a notable extension in the duration of the circadian cycle. Such an occurrence infers that transformation, which depends on RAS , hinders the expression of circadian genes [ 159 ]. Notably, cells exhibiting Per2 mutations or Cry1/2 deletions have shown susceptibility to transformation by H-RAS. Conversely, mouse embryonic fibroblasts (MEF) displaying Bmal1 deletions or clock mutations have demonstrated resistance to oncogene-induced transformation [ 160 ]. This RAS-mediated transformation relies on the activation of transcription factor 4 (ATF4) to suppress the activation of cell cycle regulators and tumor suppressor genes p16INK4a and p19ARF [ 161 ]. Utilizing a genetically engineered mouse model (GEMM), it was observed that CRDs expedited tumor development in cases where tumors manifested themselves gradually over a course of several months [ 125 ]. The RAS signaling pathway and its downstream mitogen-activated protein kinase (MAPK) pathway were found to regulate circadian rhythms in Drosophila animal experiments, and the MAPK pathway is governed by circadian oscillations [ 162 ]. Subsequent research indicated that the extracellular regulated kinase (ERK) pathway within the MAPK pathway possesses the capability to directly phosphorylate CLOCK, an action that serves to bolster the expression of biological clock genes [ 163 ]. Glycogen synthase kinase-3 (GSK-3) is a regulator of CRY, and PER and can control the stability of CLOCK [ 164 ]. When GSK-3 is inhibited, it stabilizes the CLOCK protein. Conversely, activation of GSK-3 leads to the degradation of the CLOCK protein [ 165 , 166 ]. Spengler et al. [ 167 ] found that the inhibition of GSK-3 by RAS results in a reduction in clock degradation through phosphate degradation sites, ultimately leading to an increase in transcription that is clock dependent. These findings indicate that disruptions to the molecular processes governing circadian rhythms may yield varying outcomes on RAS -mediated transformation, potentially in a tumor-dependent manner. Thus, distinct cell types may exhibit unique responses to oncogene-driven transformation in vivo and in vitro .

Liver Kinase B1(LKB1)

AMPK is a highly conserved protein in mammalian cells that functions as a key regulator of metabolic and energy homeostasis [ 168 ]. LKB1 protein is an upstream kinase of AMPK. It has been observed that mutations or deletions of LKB1 are prevalent in malignant cells, particularly in non-small-cell lung cancer, with a prevalence of up to 35% [ 169 ]. Recent studies have shown that the tumor suppressor function of LKB1 is dependent on the activation of four subfamilies of AMPK-related kinases, which specifically include microtubule affinity-regulated kinases (Mark1-4) [ 170 , 171 ]. AMPK phosphorylates CRY1 on two serines (S71 and S280), thereby disrupting its interaction with PER2 [ 172 ], while promoting the binding of CRY1 to FBXL3, leading to CRY1 ubiquitination and degradation [ 173 ]. It is anticipated that all kinases activated by LKB1 would phosphorylate substrates exhibiting amino acid sequences similar to those phosphorylated by AMPK. However, the potential of MARKs to phosphorylate CRY1 or CRY2 remains unclear. Further research is needed to elucidate this potential and understand its implications. Recent research has revealed that the nuclear localization and activity of AMPK in mouse liver bears an inverse relationship with the intranuclear protein abundance of CRY1. Activation of AMPK results in the phosphorylation of CRY1, thereby affecting circadian rhythms [ 173 , 174 ]. Furthermore, AMPK has the capability to modulate the mRNA content of nicotinamide phosphoribosyltransferase (NAMPT). In a study using a transgenic mouse model, it was demonstrated that the level of NAMPT in skeletal muscle increases with the activation of AMPK during metabolic stress. Ultimately, the activation of NAD through the elevation of NAMPT levels by AMPK results in the regulation of circadian rhythms. This regulatory process occurs by activating silent information regulator (SIRT) activity, leading to increased control over circadian rhythms [ 175 ]. Metformin effectively reduces blood glucose levels through the activation of AMPK. Recent findings suggest that mice treated with metformin experience a shortened circadian cycle, which is attributed to the facilitation of CK1ε/δ phosphorylation by AMPK. This ultimately promotes mPer2 degradation and augments activity levels [ 176 ]. The current mechanism of the clinical application of metformin and antimetabolic therapy for antitumor treatment is to alter the biological clock by activating AMPK [ 177 ]. In summary, the reduction or deletion of LKB1 and AMPK alters circadian oscillations.

RB

RB inactivation can cause retinoblastoma in children [ 178 ]. RB inhibits cell growth by preventing adenovirus early region 2 binding factor (E2F) from activating the expression of cell cycle-promoting genes [ 179 ]. Phosphorylation of RB by cyclin-dependent kinases 4 and 6 (CDK4/6) prevents its interaction with E2F, and CDK4/6 inhibitors are effective in treating tumors with intact RB function [ 179 ]. Treatment of simulated human osteosarcoma cells (U-2OS) with chronic CRD enhances phosphorylation of CDK4/6 protein and RB [ 180 ]. The occurrence of this phenomenon can be effectively thwarted with the genetic deletions of Bmal1 , Cry1 , and Cry2 . Our latest research has indicated that both Cry1 and Cry2 exhibit interactions with various E2F family transcription factors, although only Cry2 actually promotes the ubiquitination and subsequent degradation of C-MYC [ 181 ]. Study found that both CRY1 and CRY2 can interact with E2F family members and stimulate their interactions with FBXL3 [ 141 ]. The maintenance of stable E2F4 and E2F8 levels is highly dependent on the regulation of Cry1 and/or Cry2 expression. However, the regulation of cryptochromes has less influence on the levels of E2F1 protein [ 182 ]. Cry1 and Cry2 may affect E2F-dependent transcription through direct repression, but this requires further study.

P53

P53 is a prominent oncogene, with its coding product serving as a nuclear transcription factor [ 183 ]. A common observation in tumor cells is the presence of p53 mutations or deletions which lead to aberrant metabolism, compromised cell cycle regulation, and suppressed apoptosis [ 184 ]. It was found that p53 expression has a circadian rhythm [ 185 , 186 ]. The biological clock is regulated by p53 and Per2 expression is transcriptionally controlled by p53 [ 187 ]. The p53 response element overlaps with the E-box sequence in the Per2 promoter, such that p53 occupancy blocks CLOCK:BMAL1 promoter recruitment [ 187 ]. PER2 forms a stable complex with P53, thereby preventing MDM2-mediated ubiquitination and proteasomal degradation of P53 [ 188 ]. Clock proteins play a crucial role in regulating the stability of P53 at the cellular level, resulting in the direct control of p53 . Furthermore, the discovery that p53 nuclear shuttling is induced through ectopic expression of Per2 supports this assertion [ 189 ]. Inactivation of Per2 by mutation causes delayed accumulation of p53 in tumor-bearing mice exposed to ionizing radiation, and inhibition of p53 activation leads to uncontrolled continued cell proliferation [ 153 ]. Recent findings provide additional support for the notion that PER2 stability is governed by an unconventional circadian pathway whereby MDM2, a ubiquitin ligase, directly targets PER2 [ 190 ]. Hua et al [ 79 ] revealed that elevated expression of p53 resulted in modifications of apoptosis-related genes in mice afflicted with lung cancer. Additionally, heightened mRNA and protein levels of p53 were detected in Lewis lung carcinoma (LLC) cell lines with high Per2 expression, compared to control samples. Consequently, this study has established that augmenting the expression of mPer2 can effectively impede tumor cell growth and instigate apoptosis in lung cancer-afflicted mice tumor cells, through regulation of the mitochondrial signaling pathway by p53 . Miki et al [ 187 ] found that within the suprachiasmatic nucleus (SCN), p53 binds to the Per2 promoter, preventing binding of the Per2 promoter and CLOCK/BMAL1, resulting in a suppression of Per2 expression. Moreover, it was discovered that varying levels of p53 cause a phase shift in the physiological behavior of mice. It is deduced that p53 has the ability to influence the expression of the Per2 gene and its protein product, and thus, impact circadian rhythms by regulating Per2 . Two complementary research studies verified that the PER2 protein in the cytoplasm can form a dimer with P53, thereby stabilizing P53 and facilitating its entry into the nucleus, both under normal and genotoxic stress conditions [ 188 , 191 ]. Thus, there is a bidirectional regulation between p53 and Per2 [ 93 ]. Recent research has indicated that the downregulation of the Bmal1 gene in pancreatic cancer cells stimulates cell growth. Conversely, the over-expression of Bmal1 hinders cell cycle and proliferation control in a p53 -dependent fashion [ 192 ]. The data presented indicates an alternative function for clock proteins in the modulation of P53. The observed variations in clock-mediated P53 activity could be ascribed to the diverse roles of P53 in UV stress, DNA damage response, DNA repair, or cell type-specific apoptotic pathways [ 193 - 196 ].

Correlation between dysregulated signaling pathways in CRD and tumorigenesis

CRD is not only closely related to these common oncogenes and tumor suppressors genes, but also participates in crosstalk with some signaling pathways [ 20 ]. It has been reported that there is a two-way crosstalk between the biological clock mechanism and Wnt/β-catenin signaling, especially in colorectal cancer [ 197 - 199 ]. Enhancement of β-catenin signaling through interaction with an F-box protein of the Skp1-cullin 1-F-box (SCF) ubiquitin E3 ligase family called β-TrCP destroys the stability of PER2 protein levels in the intestinal mucosa [ 200 ]. The present studies highlight a bidirectional communication between the β-catenin signal and the diurnal molecular mechanism in the gut. The involvement of clocks in Wnt/β-catenin signal-dependent cancers remains an open question. Notably, Wnt signaling plays a critical role in cellular differentiation and tissue formation [ 201 , 202 ]. Through the utilization of a three-dimensional in vitro organ model to examine ordinary intestinal stem cells, it was discovered that the cellular circadian clock effectively obstructed the advancement of mouse epithelial cell cycles via its dependence on the secretion of Wnt [ 203 ]. In addition, the destruction of the biological clock can lead to the division of normal intestinal stem cells in drosophila melanogaster [ 204 ]. As a result, disturbing the biological clock can lead to upregulation of Wnt signaling, thereby altering the control of intestinal stem cell proliferation. Although the biological clock is related to cancer stem cells, the exact role and detailed molecular mechanism of the biological clock in different types of cancer are unclear [ 205 , 206 ]. Estrogen receptor α (ER α) is closely related to hormone-dependent breast cancer and the biological clock [ 207 ]. The CLOCK protein interacts with ER α, whose activity is potentiated by estrogen. This hormone stimulates the overall number of clocks, leading to an increase in clock-dependent transcriptional activity, enhancing ERα-mediated transcription, and ultimately promoting proliferation in breast cancer cell lines (MCF7 and T47D) [ 208 ]. Intriguingly, PER2 has been reported to modulate the stability of ER α protein levels, and estrogen is known to trigger PER2 expression, which suggests a regulated feedback mechanism [ 94 ]. In addition, PER1 has been reported to inhibit the transactivation of androgen receptor (AR) through direct interaction, and the ectopic expression of PER1 in human prostate cancer cells (LNCaP) reduces the expression of known AR target genes [ 94 ]. While the results obtained are noteworthy, there is still ambiguity regarding the interplay between the biological clock and nuclear hormone receptors within the human body. Specifically, the influence of progesterone receptor circadian rhythm in regulating breast cancer requires further evaluation. Furthermore, although thyroid hormone secretion remains consistent throughout the diurnal cycle, the oscillation of thyroid hormone receptor α and β expression remains dynamic. As such, additional inquiry is required to shed light on these internal associations.

CRD and tumor metabolism

Recent research suggests that the biological clock plays a critical role in regulating cell metabolism through chromatin remodeling [ 2 , 209 - 211 ]. Clock-mutant mice are susceptible to obesity and exhibit symptoms of metabolic syndrome, which may include elevated blood lipids, hyperglycemia, and liver steatosis [ 212 ]. The strong correlation between the biological clock and metabolism is underscored by these findings. While a comprehensive understanding of how clock proteins regulate metabolism remains elusive, prevailing evidence suggests that chromatin remodeling plays a critical role. Consequently, some clock regulators may be influential at the intersection between epigenetics and metabolism [ 213 , 214 ] ( Fig. 3 ).

The role of CRD in cancer metabolic reprogramming

Cancer cells exhibit a vast spectrum of metabolic irregularities [ 215 ]. The most prominent metabolic characteristics of cancer cells are aerobic glycolysis (Warburg effect), glutamine oxidation, lipogenesis and increased nucleotide synthesis [ 216 ]. Mouse embryonic fibroblasts isolated from Bmal1 -/- mice showed high glycolysis, increased lactic acid production, and decreased lipid oxidation and ATP production, similar to the metabolic characteristics of cancer cells [ 217 ]. It is noted that a clock-mediated glycolysis state similar to that seen in tumors can potentially be achieved through transcriptional regulation of genes that encode glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) [ 217 ]. A number of genes, whose protein products play vital roles in metabolic processes, demonstrate a circadian rhythm in their expression. These encompass glucose-6-phosphatase and PCK2, which are involved in gluconeogenesis, pyruvate kinase, which is responsible for glycolysis, glucokinase, involved in glycogen synthesis, glucose transporter 2, which facilitates glucose transport, and HMG-CoA reductase, which participates in cholesterol metabolism [ 218 ]. A recent investigation has revealed that malignant cells exhibiting an elevated CRDscore are distinguished by the activation of crucial metabolic pathway glycolysis, as well as the epithelial-mesenchymal transition pathways [ 219 ]. Meanwhile, the ongoing development of biomarkers linked to circadian rhythms holds considerable promise in the realm of prognosticating tumor outcomes and assessing the effectiveness of immunotherapy [ 220 ]. Recent research has discovered that the absence of BMAL1 has a disruptive effect on the synchronization of biological rhythms and amplifies the manifestation of fibrotic characteristics in various types of tumors. As a consequence, this abnormality triggers the proliferation of cancer-associated fibroblasts (CAFs) [ 215 ]. CAFs are responsible for inducing a series of metabolic alterations, ultimately fostering the spread of tumors and tumor immune evasion [ 221 ]. The acceleration of Apc-driven colorectal cancer (CRC) pathogenesis in vivo was observed through the utilization of an intestinal organoid model. It was found that CRD is responsible for this acceleration. The APC-mediated hyperactivation of Wnt signaling was identified as a key factor in this process. This hyperactivation leads to the up-regulation of c-Myc , a well-known target of Wnt signaling, which subsequently drives an increase in glycolytic metabolism [ 222 ]. Recent studies have provided evidence suggesting that CRD is linked to a heightened susceptibility to obesity and obesity-related ailments [ 223 - 225 , 226 ]. It has been established that perturbations in the circadian rhythm play a pivotal role in tumor development and are correlated with an increased occurrence and progression of various cancers, including breast, prostate, colorectal, and thyroid cancer [ 227 ].

The expression of several nuclear receptors, including peroxisome proliferator-activated receptor family members (PPAR α, PPAR γ and PPAR δ) and estrogen related receptor family members (ESRR α, ESRR β and ESRR γ), is specific to different tissues [ 228 ]. PPAR γ coactivator 1 α (PPARGc1 α), which follows a circadian expression pattern in metabolic tissue, plays a crucial role in exercise activity, body temperature regulation, and metabolic rates, and its absence in mice can lead to defects in these areas [ 229 ]. Disruptions in regulatory factors such as SIRT1, an essential deacetylase involved in various biological activities, can result in metabolic pathway defects, proliferation, and ultimately cancer. SIRT1 plays a significant role in metabolism by deacetylation of several proteins and histone deacetylation to regulate gene expression [ 230 ]. SIRT1 regulates tumor-related metabolism by deacetylating LXR and FOXO1, which affects lipid metabolism and insulin sensitivity. This regulatory mechanism significantly influences cell proliferation and survival in cancer cells [ 231 - 233 ]. One of the attractive features of SIRT1 is that it depends on the enzyme activity of NAD + [ 234 ]. The diurnal oscillation of SIRT1 activity showed that the intracellular NAD + level could also oscillate ( Fig. 4 ). A study showed that NAD + levels show bimodal oscillations in the mouse liver [ 235 ]. The biological clock controls the expression of NAMPT, which is the key rate-limiting enzyme in the remedial synthesis pathway of NAD + [ 235 , 236 ]. Intriguingly, another NAD + -dependent enzyme, poly (ADP-ribose) polymerase (PARPs), has been shown to interact functionally with SIRT1 [ 237 ]. Given the direct control of SIRT1 deacetylase activity by NAD + , circadian regulation of NAD + levels appear to be an important regulatory mechanism controlling circadian rhythms, metabolism and cell growth. Intriguingly, alterations in NAMPT levels are associated with metabolic disorders and cancer [ 238 ], while FK866 (a highly specific NAMPT inhibitor that abolishes NAD + circadian oscillations and SIRT1 cycle activity) can induce apoptosis in human cancer cells [ 236 , 239 ]. However, further studies are needed to reveal the exact role of circadian rhythm control of SIRT1 activity in the regulation of metabolism and tumorigenesis.

Crosstalk between hormones and the circadian clock

Certain genes demonstrate a circadian expression pattern and the proteins resulting from them assume pivotal functions in metabolic processes such as glucokinase, glucose-6-phosphatase, pyruvate kinase, glucose transporter 2, and HMG-CoA reductase. As the SCN regulates daily fluctuations in hormone production and secretion, specifically melatonin and corticosteroids, disturbances in the circadian rhythm cause corresponding changes in their circulating levels [ 240 ]. The control of melatonin levels is governed by central pacemakers in the SCN, which operate through polysynaptic pathways. This hormone is inhibited by light [ 241 ]. One of the roles of melatonin is to regulate glucose homeostasis, which in turn prevents cell and tumor growth [ 242 - 244 ]. The literature indicates that prolonged exposure to low light conditions is an apparent contributing factor in the growth of liver cancer and the synthesis of mammary epithelial cells. This is attributed to the inhibition of melatonin synthesis [ 245 , 246 ]. Various epidemiological investigations have shown a consistent correlation between high melatonin levels and a lower incidence of cancer. These findings provide credible evidence supporting the potential role of melatonin in suppressing tumor growth [ 247 , 248 ]. Aligned with this finding, the administration of melatonin has been shown to decrease estrogen levels and impede DNA synthesis in breast tissue [ 249 ]. Disruption of the circadian rhythm of glucocorticoid levels is believed to be a potential factor in the development of tumors. The production of adrenal glucocorticoid is primarily controlled by the hypothalamic-pituitary-adrenal axis, while intrinsic clocks located within the adrenal gland and the sympathetic nervous system also regulate glucocorticoid levels [ 250 - 253 ]. When the SCN is disrupted, the circadian rhythm of glucocorticoid levels becomes disturbed, potentially harming clock oscillations and increasing the risk of tumorigenesis [ 254 ]. Additionally, epidemiological studies have shown that glucocorticoids may play a part in stress-related cancer progression [ 255 ]. From a mechanistic standpoint, the transcriptional regulator TSC22D3 appears to be a key player in impeding treatment-induced anticancer immunity when stress-induced increases in glucocorticoids occur. Changes in glucocorticoid levels may also affect lymphocyte function, thereby impacting antitumor immunity [ 256 , 257 ]. Moreover, cryptochromes, which evolved from bacterial light-activated DNA repair enzymes [ 258 ], have been shown to contribute to various cellular functions that may influence cancer growth, in addition to generating circadian rhythm [ 182 ].

CRD and tumor immune response

The immune system comprises immune organs, immune cells, and immune active substances, serving immune surveillance, defense, and regulation functions [ 259 ]. The expression of circadian rhythm genes is widespread in most immune cells, resulting in diurnal changes in the functioning of both innate and adaptive immune cells [408, 260 ]. The rhythmic expression of immune cell clock genes has profound implications on immune cell function, including the generation of daily rhythms in cytokine and chemokine synthesis and release [ 260 - 263 ]. Recent studies have shed light on the involvement of biological rhythms in the regulation of the immune system [ 264 - 266 ] ( Fig. 5 ).

It is worth noting that diurnal rhythms impact not only immune cells, but also levels of immune effector molecules [ 267 ]. Disruptions to the circadian clock can therefore lead to disruptions in immune rhythms, potentially impairing normal immune responses. Notably, disruption of the circadian rhythm has been linked to several dysfunctions in intestinal intraepithelial lymphocytes, including the promotion of regulatory B cell dysfunction and CD4 + T cell apoptosis, ultimately leading to enteritis [ 268 ]. Abnormal biological rhythms can compromise the immune system and further facilitate tumor growth [ 15 ]. In rats subjected to a chronic shift model, disrupted biological rhythms led to rhythm disorder of cytolytic function in natural killer (NK) cells, as evidenced by the altered expression of NK cell clock genes Per2 and Bmal1 . This, in turn, promoted the growth of intravenously injected MADB106 tumor cells in the lung [ 269 ]. The innate immune system's macrophages also exhibit rhythmic oscillations that are regulated by the biological clock and play a critical role in tumor immunity [ 15 ]. CRD can contribute to tumorigenesis and development by hindering adaptive immunity. The CD4 + /CD8 + T cell ratio in the breast cancer tumors of mice with rhythm disorders increases, while the immunosuppressive CD4 + FoxP3 + Treg is notably enhanced, resulting in the elevation of the Treg/CD8 + T cells ratio, creating an immunosuppressive microenvironment that advances the malignant progression of breast cancer [ 270 ].

Recent research demonstrates that the inner core rhythm genes of tumor cells are extensively dysregulated. Gene correlation analysis indicated that the immune checkpoints of tumor cells, such as programmed cell death 1 ligand 1 (PD-L1), PD-L2, PD-1, CTLA-4, and TGF-β1, display a positive correlation with the expression of core rhythm genes. Furthermore, ChIP-seq data in normal mouse liver indicates that the regulation of PD-L1 transcription is guided by biological rhythms [ 271 ]. There is a speculative notion that the rhythm disorder found in tumor cells has the potential to affect the expression of immune checkpoint molecules, which could facilitate tumor immune escape. However, further experimental evidence is required to substantiate this claim. Recent in vivo observations confirm the existence of cytokine secretion rhythms, indicating that when wild-type mice were transferred to the dark phase, the serum levels of IL-6, IL-12, CCL5, chemokine (C-X-C motif) ligand 1 (CXCL1), and C-C motif chemokine ligand 2 (CCL2) were all elevated after lipopolysaccharide (LPS)-induced stimulation [ 272 ]. An alternative explanation for the rhythmic production of cytokines may be linked to the regulation of glucocorticoids, which can suppress the production of inflammatory mediators in macrophages and are also subject to circadian rhythms. It is probable that the circadian clock plays a crucial role in regulating these oscillations [ 273 , 274 ]. Gibbs et al. [ 275 ] discovered that mice with myeloid-specific Bmal1 deletion did not show any changes in the levels of IL-6 serum, induced by Lipopolysaccharide (LPS). The study further explored the potential association between REV-ERBα and the circadian and inflammatory pathways, where the expression of the regulatory factor REV-ERBαwas found to be temporally regulated in peritoneal macrophages, which was disrupted with Bmal1 depletion. Notably, REV-ERBα deficiency led to the cessation of rhythmic immune responses to LPS, indicating a potential interrelation between BMAL1, REV-ERBα, and IL-6 production in macrophages. Mice exhibiting a deficiency in Per1 and Per2 displayed heightened levels of IL-1β and TNF-α expression during both basal states and LPS stimulation [ 276 ]. Additionally, removal of the clock genes Cry1 and Cry2 resulted in a prolonged elevation in the expression of IL-6, IL-1β, and TNF-α [ 277 ].

In normal physiological circumstances, the immune system experiences daily oscillations in its composition and function, which is governed by the biological clock system. The system effectively combats invading pathogens, damaged cells, and tumor cells, thereby preserving the body's overall well-being. However, if the feedback mechanism of the circadian clock is compromised, the immune system may remain persistently suppressed, thus diminishing its ability to eliminate tumors effectively. In addition, the disruption of rhythm in tumor cells may facilitate their immune-evading mechanism. Thus, the disruption of immune regulation caused by rhythm disorder is a crucial factor in the emergence and progression of tumors.

The role of CRD in tumor therapy

Chronochemotherapy and CRD

The efficacy of drugs and their associated side effects are key considerations when implementing a chemotherapy regimen for cancer patients [ 17 ]. Chronochemotherapy, which entails adjusting drug administration in accordance with biological rhythms, can not only enhance drug efficacy but also mitigate adverse reactions [ 278 - 280 ]. Chronochemotherapy involves administering medication at the optimal phase of the circadian rhythm to achieve maximal efficacy. Studies conducted previously have found that the timing of medication is a contributing factor to the survival rate of children diagnosed with acute lymphoblastic leukemia. Specifically, administering 6-mercaptopurine and methotrexate at night resulted in a 5-year survival rate of 80%, whereas administering these drugs in the morning yielded a significantly lower rate of only 40% [ 281 ]. As a result, regular maintenance chemotherapy has been widely accepted as the preferred approach to treating acute lymphoblastic leukemia in children. The effectiveness of anticancer drugs is frequently hindered by their undesirable side effects and toxicity. Chronochemotherapy offers a solution to this issue by providing a means to reduce adverse effects. One promising approach involves the use of a newly developed oral fluoropyrimidine drug which is designed to be released after a predetermined delay, thereby reducing potential negative effects [ 11 ]. Another study entailed conducting an irinotecan pharmacokinetics evaluation and toxicity assessment on 31 cancer patients. The patients who received the drug through the second method of administration experienced less severe diarrhea during regular drug administration. This finding highlights the effectiveness of chronochemotherapy in reducing the adverse reactions of drugs [ 282 ]. Furthermore, chronochemotherapy shows promise in enhancing the survival rate and quality of life of cancer patients by mitigating the cytotoxic effects of anticancer drugs [ 283 - 285 ]. Various phase I to phase III clinical trials have also indicated the efficacy of chronochemotherapy in treating diverse types of tumors [ 286 , 287 ]. From a mechanistic standpoint, certain anticancer medications have demonstrated heightened cytotoxicity toward cells during specific phases of cellular division. This indicates that optimizing dosing intervals based on circadian rhythm-related drug properties could potentially lead to favorable clinical outcomes for patients [ 288 , 289 ]. While the liver is a well-known rhythmic organ, it has been observed that livers with tumor metastases do not exhibit a distinct circadian rhythm. However, administering anticancer drugs directly into the hepatic artery in a time-regulated manner has shown beneficial effects in patients with liver metastases [ 290 , 291 ]. In an international clinical trial, this approach proved to be a safe and effective therapy [ 292 ].

However, findings from a small study [ 293 ] advocating for the effectiveness of chronotherapy in ovarian cancer were not replicated in subsequent larger studies [ 294 , 295 ]. It is pertinent to note that a sizable European investigation [ 296 ] on the effects of chronochemotherapy on colorectal cancer did not yield any beneficial outcomes for the study population as a whole. It is worth mentioning that while chronochemotherapy showed favorable results for male patients compared to conventional treatment modalities, the utilization of chronotherapy by female patients resulted in a concerning 38% increase in mortality [ 297 ]. This suggests that chronochemotherapy may be harmful to specific populations and provides important experience for subsequent clinical trials of chronochemotherapy. It also suggests that the empirical use of chronochemotherapy in cancer treatment has not yielded sufficiently consistent results to justify routine clinical use. The real application of chronochemotherapy in cancer treatment is still in its infancy. More clinical trials are needed to expand its clinical application, particularly in optimizing treatment schedules, understanding patient-specific circadian rhythms, and investigating the effects of chronochemotherapy across different age groups and genders.

Targeting core elements of the biological clock in tumor therapy

In recent decades, an increasing number of minor molecules have been found to regulate circadian rhythms with the ability to interact with either core or non-core clock proteins. For example, small molecules such as KL001, which stabilizes the CLOCK protein, and SR9009, an agonist of REV-ERB, have shown significant effects on the circadian clock mechanism. These molecules can modulate the activity of core circadian proteins and thus influence the overall circadian rhythm [ 298 , 299 ] ( Fig. 6 ). This discovery brings about a broader spectrum of treatment options for patients dealing with clock-related disorders [ 300 ]. Recombinant cortistatin (CORT) protein stabilizers have been proven to enhance glucose tolerance and extend circadian rhythm [ 301 , 302 ], and conversely, inhibitors of its transcriptional repressive activity have shown a hindrance in the growth of breast cancer cell lines [ 303 ]. Emerging studies report that the pharmacological suppression of RORγ exhibits considerable anti-tumor efficacy in various cancer types, including pancreatic and triple-negative breast cancer, both in vitro and in vivo [ 304 , 305 ]. Additionally, the use of synthetic RORγ agonists has demonstrated a capacity to bolster antitumor immunity by augmenting cytotoxic lymphocyte function while decreasing immunosuppressive mechanisms [ 306 ]. XY018 and SR2211, which are RORγ-selective antagonists, were found to inhibit the proliferation of prostate cancer cells expressing the androgen receptor. Furthermore, these antagonists restored sensitivity to treatment with enzalutamide, a popular androgen inhibitor for prostate cancer. Enzalutamide induces apoptosis and reduces the expression of key proliferation and survival proteins, both of which have been identified as critical events in treating this condition [ 304 ]. RORγ agonists have been demonstrated to be effective in modulating diverse signaling pathways to improve the immune system's antitumor response to leukemia, colon cancer, and breast cancer [ 307 - 309 ]. LYC-55716, a ROR receptor agonist, has undergone rigorous preclinical and clinical testing and has shown excellent tolerability, safety, and pharmacokinetics in isolation or when combined with conventional immunotherapy drugs [ 310 ]. Nobiletin has been identified as an agonist of RORα and RORγ, exhibiting various crucial anticancer properties. This compound exhibits the potential to initiate apoptosis and cell cycle arrest, while also upregulating tumor suppressors and inhibiting the expression of oncogenic factors. Furthermore, it can suppress migration and invasion while increasing chemosensitivity in various types of cancer cells [ 311 ]. These findings substantiate the hypothesis that ROR subtypes could be a valuable target for developing effective cancer treatments.

The function of CRY1 and CRY2 in suppressing clock-regulated gene transcription through direct interaction with the BMAL1/CLOCK complex is a significant aspect worth noting [ 312 - 315 ]. KL001 was identified as the first compound to bind to and stabilize CRY by preventing FBXL3-mediated ubiquitin-dependent degradation [ 301 ]. According to recent research, administration of KL001 has been shown to decrease the expression of OLIG2 and SOX2 in healthy brain cells, deter the proliferation of GSCs, and mitigate their toxicity [ 316 ]. Intriguingly, in vitro assessments indicated that pharmacologically targeting CRE through KS15 resulted in diminished proliferation among MCF-7 breast cancer cells, as well as heightened receptivity to doxorubicin and tamoxifen. Conversely, no harmful effects were observed in normal breast epithelial MCF-10A cells [ 303 ]. Given these contradictory outcomes, it is imperative that further research is conducted to discern whether CRY holds potential as a new therapeutic avenue.

The nuclear receptors, REV-ERBα and REV-ERBβ, play a pivotal role not only in the molecular circadian clock but also in metabolic regulation [ 9 , 317 ]. The expression of REV-ERBS irregular in various cancer types, where it primarily influences blood glucose levels, blood lipids, and energy metabolism [ 318 ]. Notably, the administration of REV-ERB agonists elicits a dramatic response in mice, including the selective destruction of cancer cells [ 319 ]. The antitumor effects of REV-ERB agonists SR9009 and SR9011 were further confirmed by subsequent studies, and treatment with these drugs resulted in a significant reduction in the proliferation and viability of glioma cells, while also inhibiting the growth of both chemoresistant and chemosensitive tumors by impeding autophagy in lung cancer cells [ 320 , 321 ]. Additional studies have demonstrated that autophagy and de novo lipogenesis play critical roles in eliciting apoptotic responses in malignant cells treated with SR9009 and SR9011 [ 319 ]. Additional chemical agonists directed towards REV-ERBα, such as GSK2945, GSK0999, GSK5072, and GSK2667, have undergone development. However, further investigation is necessary to determine their impact on cancer [ 322 ].

Casein kinases 1δ and 1ε (CK1δ/ε) are key components of the circadian clock, regulating their timed nuclear import activity through the phosphorylation of PERs to determine circadian rhythms [ 323 ]. In recent years, casein kinases have been recognized as oncogenic proteins and have become therapeutic targets for cancer [ 324 ]. A series of potent and selective CK1δ/ε inhibitors have been demonstrated to have antitumor effects on breast cancer both in vivo and in vitro [ 325 ]. Additionally, a separate investigation revealed that the CK1δ/ε inhibitor IC261 exhibited significant suppression of colon, liver, and other human cancer cell survival and proliferation while promoting apoptosis, a key factor in multiple carcinogenic mechanisms [ 326 ]. Apart from research initiatives aimed towards the CK1 family, a recent study utilizing cell-based screening techniques has highlighted the discovery of a novel and efficacious CK2 inhibitor (GO289), exhibiting exceptional potency and selectivity. Its application has been found to considerably extend circadian rhythms and impede the proliferation of various human and mouse cancer cells [ 327 ]. A number of preclinical and clinical studies have indicated that several anticancer drugs targeted at the CK1 or CK2 family, such as umbralisib and CX4945, exhibit distinct immunomodulatory effects in the management of hematological malignancies such as chronic lymphocytic leukemia, myeloid dysplastic syndromes, acute myeloid leukemia and multiple myeloma (MM) [ 328 , 329 ]. Altogether, these results suggest that targeting CK family members is a promising therapeutic approach for the treatment of various cancers.

Circadian rhythm and hormone

Several experimental and clinical studies have demonstrated that melatonin possesses strong anticancer properties in conjunction with non-pharmaceutical interventions [ 330 ]. A meta-analysis showed that low melatonin secretion was associated with higher cancer incidence in patients exposed to light at night [ 331 ]. Furthermore, it should be noted that melatonin demonstrates a targeted affinity towards cancer cells, while leaving normal cells unaffected [ 332 ]. Additionally, melatonin serves to mitigate the harmful impact of chemotherapy on normal cells by restoring the light/dark circadian rhythm [ 333 ]. These findings suggest that melatonin therapy has the potential to become a highly secure chronobiological approach to treating cancer. Similar to melatonin, glucocorticoid (GC) is also an anticancer hormone [ 334 ]. GCs show remarkable efficacy in treating lymphoid malignancies such as leukemia, lymphoma, and multiple myeloma. Significant efforts have been made to augment their effects and surmount drug resistance [ 335 ]. Intriguingly, recent research highlights that enhanced circadian clock treatment with dexamethasone in mice reduces melanoma tumors [ 336 ]. Although GCs have a tumor-suppressive role, there have been recent clinical observations indicating that they may not be responsive to immune checkpoint inhibitors (such as anti-PD-L1), possibly due to their immunosuppressive effect resulting in inadequate tumor proliferation and growth [ 310 ]. Given the diurnal fluctuations in endogenous GC levels, it is imperative to take into account the dose and administration timing of corticosteroids to enhance the effectiveness and safety of immune-based cancer therapy.

Conclusion

Over the past few decades, extensive chronobiological research has significantly increased our comprehension of the operative functions and mechanisms of circadian clocks in human health and disease, specifically cancer. Interference with circadian rhythms can have adverse effects on both the molecular clocks of tumors and the host's circadian systems, thereby increasing the risk and progression of cancer. It is plausible to suggest that multiple pathways controlled by the circadian clock are utilized by cancer cells as they consume nutrients at a high metabolic rate. This article examines the interdependent relationship between non-clock transcription factors and circadian rhythm-related hormones with the circadian clock in order to establish the correlation between circadian rhythm and tumor metabolism. The circadian rhythm exerts a significant influence on the immune system and its response to tumor cells. Moreover, it is plausible that CRD may facilitate tumor growth and immune evasion by regulating cell cycle regulators and immune response. Further, we provide an overview of the potential application of circadian rhythm in tumor therapy, such as chronochemotherapy and targeting biological clock components and related hormones. However, current research is in its nascent stage, and more clinical trials are necessary to validate its benefits. Given that endocrine tissues play a pivotal role in the circadian regulation of systemic physiology, diagnosing and treating circadian endocrine imbalances could enhance the wellbeing of cancer survivors. In summary, the integration of circadian rhythms with medicine holds enormous potential to enhance cancer care and prevention by optimizing treatment timing, improving therapeutic efficacy, and reducing side effects, ultimately leading to better patient outcomes and quality of life.

Competing interests

All authors declare no potential conflict of interests.

Authors' contributions

Y.Z. and R.D. wrote the manuscript. Y.Z. and Y.Z. designed the Figs. X.G designed the study and edited the manuscript. All authors read and approved the final manuscript

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