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Introduction

The behavioral activities and internal physiology of organisms exhibit distinct circadian rhythms, which are caused by the 24-h circadian cycle resulting from Earth's rotation (1,2). The periodic changes in the external environment of organisms are transmitted into the body, which has independently evolved a circadian rhythm system to adapt to these changes (3,4). Further investigation has shown that the circadian rhythm system couples the external environment and internal physiology through complex mechanisms rather than a passive response to changes in the external environment. This complex interplay not only endows organisms with greater adaptability and survival advantages in their external environment but also ensures the precision of the continuous operation of the body (5).

Transitioning from the theoretical to the practical implications of this understanding, circadian rhythms are closely related to the health of the human body (6,7). Based on substantial evidence from studies (8–11) on human cancer and animal experiments, the International Agency for Research on Cancer has classified night shift work as a probable human carcinogen in Group 2A (12). Epidemiological and experimental studies have shown that the circadian clock influences several physiological pathways and that their disruption can lead to various health issues, including cancer (13,14). To further emphasize the relevance of this issue in daily lives, the wide range of connections between these findings and the living habits of modern society need to be considered. The disruption of circadian rhythms in modern life is not limited to night-shift work; jet lag, exposure to nighttime light, electronic devices and mistimed eating can disrupt the circadian rhythm (15). This phenomenon is common in modern life and highlights the need to understand the mechanisms of action behind disorders involving the circadian rhythm. However, the mechanism by which circadian rhythm-related disorders affect cancer is not clear. The correlation between these activities and cancer, along with the underlying intrinsic mechanism, need to be determined.

The present review synthesizes emerging evidence from in vitro mechanistic studies and clinical observational data to propose molecular pathways linking circadian disruption to cancer progression, especially the Period (PER) gene family The PER proteins constitute the circadian output arm of the clock and function as repressors of heterodimeric clock circadian regulator (CLOCK)-basic helix-loop-helix ARNT like 1 (BMAL1). Their expression profiles and roles in cancer have been investigated. While certain interactions [e.g., period circadian regulator 2 (PER2)-epithelial-mesenchymal transition (EMT) and snail family transcriptional repressor 2 (SNAI2)-enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)] require further validation through biochemical assays or in vivo genetic perturbations; inclusion of these interactions aimed to highlight critical knowledge gaps and prioritize candidate mechanisms for future research, particularly in circadian-metabolic-epigenetic crosstalk.

Circadian dysfunction and cancer

Circadian clock

The circadian clock system is a complex network that integrates periodic external environmental factors with intracellular molecular operations. This sophisticated system functions through the expression and regulation of the circadian clock genes. Circadian genes are governed by interconnected oscillators and feedback loops, which function systemically at the cellular level (16). The central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus is initially concentrated at the systemic level and helps orchestrate whole-body circadian rhythms. This central clock not only generates the circadian clock but also constantly renders the system of circadian rhythm changes synchronized with the environment (16). This synchronization involves signal transmission from the external environment to tissues and cells via the autonomic nervous system and endocrine system, thereby aligning cellular oscillators with the circadian rhythm and regulating various physiological factors in the body. Although light signals are the primary external signals, the system also exhibits responsive adaptations to other types of stimuli, including dietary intake, ambient temperature changes and physical exercise; these stimuli fine-tune the internal human clock (17–20). Within the SCN of the hypothalamus, the heart of the circadian rhythm system, these additional signals generally cannot override the dominant influence of light-dark signals (16,21). This highlights the close connection of the circadian system with the light-dark cycle, extending the scope to a broader physiological context in which the effects of the circadian system occur in various tissues and organ systems in the body. Studies using circadian rhythm reporting methods have shown that tissues of most peripheral organs can independently express circadian rhythms, even in the absence of central regulation (16,22–24). This independent functionality allows these peripheral tissues to provide feedback to the central clock, completing a complex loop of regulation and synchronization.

By combining these details, a comprehensive understanding of the multifaceted nature of the circadian rhythm system may be gained, from its genetic basis to its systemic and cellular operations. By conducting further studies at the cellular level, widely distributed autonomous oscillators consisting of interconnected feedback loops were identified, each of which serves a key role in sustaining the circadian rhythm (Fig. 1). In the primary feedback loop (22), CLOCK and BMAL1 or neuronal PAS domain protein 2 (NPAS2) proteins translocate from the cytoplasm to the nucleus, where they bind to E-boxes, promoting the transcription of PER and cryptochrome circadian regulator (CRY) genes, which are key components of the circadian system. In the evening, PER and CRY protein heterodimers relocate to the nucleus, where they interact with the CLOCK and BMAL1 proteins, inhibiting their transcription (5,6). This inhibition effectively suppresses the transcription of their own genes, thereby creating a self-regulatory loop (5,6).

Figure 1. Circadian feedback loop and its correlation with cancer. (A) Nighttime light, waking up at night and eating late at night can increase the susceptibility to cancer. Morning and evening activity can reduce cancer susceptibility. (B) Circadian transcriptional and translational feedback loop machinery in mammals. PER, period circadian regulator; CRY, circadian regulator; BMAL1, basic helix-loop-helix ARNT like 1; CLOCK, heterodimeric clock circadian regulator; RORs, RAR related orphan receptor; REV-ERB, nuclear receptor subfamily 1 group D member 1; NFIL3, nuclear factor, interleukin 3 regulated; DBP, D-box binding PAR BZIP transcription factor.

In the second feedback loop within the nucleus (22), BMAL1/CLOCK heterodimers activate the transcription of nuclear receptor subfamily 1 group D member 1 (REV-ERB) and RAR related orphan receptor (ROR) genes. RORα and REV-ERBα constitute a supplementary loop, which acts through RORE elements present in the BMAL1 promoter to activate or inactivate BMAL1 transcription, respectively. Finally, the third feedback loop involving proline and acidic amino acid-rich basic leucine zipper (PAR-bZIP) proteins, including DBP, TEF and HLF, which interact with the repressor nuclear factor, interleukin 3 regulated at sites containing D-boxes, is driven by the aforementioned REV-ERB/ROR cycle (5,22).

Epidemiological studies on circadian rhythms

Following the classification of night shift work as a probable carcinogen (Group 2A) by the International Agency for Research on Cancer (12), recent studies (25–27) have confirmed the close association between long-term night shift work and the incidence of cancer. This notable development in the field of occupational health has led to more focused investigations, with studies on breast, colorectal, skin, ovarian and prostate cancer showing that long-term night shift work increases susceptibility to cancer (25,28–31). These findings highlight the strong effect of altered circadian rhythms on health, with multiple factors contributing to deviation from normal circadian rhythms in individuals engaged in long-term night shift occupations (Fig. 1), including fragmented sleep patterns, disordered eating habits, exposure to nocturnal light and activity, tobacco use, alcohol consumption and even exposure to carcinogens (25,28–31). When the focus is shifted to environmental factors, the light-dark environment serves a key role in modulating the circadian clock. In this context, several studies have shown a significant association between exposure to artificial light at night (LAN) and an increase in the risk of cancer. This correlation was found across various types of cancer, including prostate, breast, colorectal, thyroid and pancreatic cancer (28,32–36). The interaction of light with the central clock in the SCN of the hypothalamus and subsequent effects on the peripheral clock leading to cancer illustrate a direct association between environmental factors and physiological responses. A further study of epidemiological evidence indicates that light disruption can lead to circadian rhythm-related disorders in n organs and tissues, thereby increasing susceptibility to cancer (37). This finding highlights the importance of studying the relationship between exposure to light at inappropriate times and the risk of cancer.

Studies on nighttime sleep duration have shown no correlation with risk of cancer (prostate and breast cancer), but behaviors such as frequently waking up at night in the previous year are significantly associated with a greater risk of prostate and breast cancer (38–40), which may be caused by sleep problems due to circadian rhythm disturbances resulting from preexisting diseases. Sleep duration at night shows regional differences. Studies have shown that in Asia, when sleep time is too short (<7 h of total sleep among men and overweight individuals), there is a significant correlation with cancer. However, studies from Spain and the UK found no correlation between the duration of sleep and the risk of cancer (38,39). Another recent case-control study reported a significant correlation between shortened sleep duration and the risk of breast cancer (41,42). These regional differences occurred due to variations in susceptibility or recall bias, highlighting the need for further investigation into whether the effect of circadian rhythm disturbances differs among populations. Population-scale genomic studies have identified inherited variants that disproportionately increase cancer risk in specific ethnic groups. For example, BRCA1/2 pathogenic variants are more prevalent in certain Indian subpopulations and are correlated with higher hereditary breast/ovarian cancer risk (43). Similarly, cystic fibrosis transmembrane conductance regulator mutations in Chinese patients with pancreatic cancer highlight population-specific driver genes (44). These findings emphasize the role of germline genetic variability in shaping cancer susceptibility.

The relationship between dietary patterns and cancer risk also warrants attention, with studies on disordered eating showing that late-night eating increases the risk of prostate, breast and colorectal cancer (45–47). This finding may be confounded by mistimed light exposure, as late-night eating implies longer exposure to nighttime light. Additionally, extending nighttime fasting reduces the risk of breast cancer recurrence (48), further supporting the association between circadian rhythm disturbances and the occurrence, development and recurrence of cancer. Not only circadian rhythm disruption but also a poor diet, including the consumption of fast food, canned goods and excessive sugar, experienced during stressful night shifts are associated with cancer development in night shift workers (49,50). An optimal nutritional regimen should systematically integrate key biological parameters, including chronological age, metabolic status and neurocognitive expenditure. This adaptive framework must concurrently consider occupational energy expenditure patterns, circadian rhythm variations and psychosocial stressors. Consequently, effective dietary prescriptions require meticulous evaluation of individual anthropometric measurements, habitual activity profiles and biochemical markers to ensure congruence with organismal homeostasis and sustainable health outcomes (49). These epidemiological findings highlight the harmful effects of disrupting circadian rhythms, with most disorders leading to an increase in cancer susceptibility focused on the diurnal cycle transition phase of the circadian rhythm, suggesting that this may be a particularly vulnerable period in the circadian rhythm system and a key phase for circadian rhythm-related disturbances to affect the health of individuals. This means that the process of transitioning from one daily activity pattern to another makes organisms more susceptible to disturbances from abnormal behavior, which in turn can disrupt their circadian rhythms. Such disruptions can break down the internal time-regulation systems of organisms, leading to various negative consequences (51). Therefore, proper synchronization of the circadian rhythm is key for maintaining health and preventing diseases.

Circadian rhythm disruption in cancer animal models

Animal models can be used to validate epidemiological results and are essential for further understanding the association between circadian rhythm disruption and cancer. By disrupting the circadian rhythm of mice through a chronic jet lag protocol, it was found that mice presented higher tumor growth rates, greater tumor numbers and more metastatic sites compared to the control group, leading to more palpable masses at early stages and larger terminal tumor volumes (52–54). As nocturnal animals, mice exposed to LAN exhibit suppressed locomotor activity via negative masking (for example, a 75% reduction under direct illumination) and disrupted circadian rhythms, manifesting as delayed activity onset and aberrant phase-shifting responses (55–57). LAN also induces anxiety-like behaviors (such as reduced open-field exploration) and transient spatial memory impairment (58–60). These findings emphasize the necessity of stringent lighting control in experimental settings, particularly for studies investigating circadian or metabolic mechanisms, to avoid confounding effects of unintended light exposure.

Disrupting the circadian rhythm of mice through exposure to artificial LAN resulted in greater tumor numbers, more palpable masses at early stages, larger terminal tumor volumes and greater weight gain and spleen enlargement (61,62). When pancreatic cancer cells lacking the BMAL1 gene were implanted into mice, mice presented faster tumor growth rates, lower survival rates and drug resistance in tumors (63). These findings confirmed the strong influence of circadian rhythm disorders on the occurrence, development and treatment of cancer. Walker et al (64) improved the understanding of the effect of circadian rhythm disorders on animal behavior through their research on disrupting the circadian rhythm with time-restricted feeding. It was reported that such disruptions cause variations in the activity cycle and vital signs of tumor-bearing mice, including daily activity patterns, body temperature rhythms and weight gain (53).

To investigate the spread of cancer, researchers induced circadian rhythm disruption in mice by implementing a chronic jet lag protocol. Analysis of blood-related pathways in tumor-bearing mice demonstrated an increase in the number of cancer cells in the bloodstream and almost a doubling of disseminated cancer cells in the bone marrow (53). This significant increase indicated a greater ability of the cancer to spread via the bloodstream under circadian rhythm disruption. Lawther et al (65) found that disruption of the circadian clock through a chronic jet lag protocol exacerbates cancer-induced inflammation and amplifies disparities in inflammatory signaling between the body and the brain. The authors also highlighted that cancer-induced inflammation is organ-specific, further complicating the interplay between cancer and the circadian clock. Hadadi et al (53) found that disrupting the circadian rhythm of mice through a chronic jet lag protocol can promote EMT and increase the efficiency of mammosphere formation in cancer cells. These disorders, induced by the chronic jet lag protocol, contribute to the tumorigenic potential and stemness of tumor cells, affecting their growth, transport and metastasis while significantly increasing the tumor burden. In mice with circadian rhythm disruption, researchers have reported a decrease in the expression of PER2, CRY2 and REV-ERB, along with a loss of rhythmicity in the BMAL1, CRY1 and REV-ERB genes (52). Analysis of white blood cells demonstrated that the clock genes CRY1, CRY2, PER2 and REV-ERBβ lost their normal rhythmicity, whereas REV-ERBα, PER3 and DBP maintained significant rhythmicity (66). This disruption in gene expression and loss of rhythmicity under conditions of circadian rhythm disruption leads to asynchrony among clock genes. This desynchrony is closely associated with the occurrence, development and treatment of cancer (67). To summarize, the use of animal models has provided invaluable insights into the complex interplay between circadian rhythm disruption and cancer, demonstrating intricate details of the molecular, physiological and behavioral changes associated with this disruption.

Changes in the immune system due to circadian rhythm disruption

Circadian rhythm disruption strongly affects tumor immunity by regulating the cytokine-chemokine network. Hadadi et al (53) reported that circadian rhythm disruption induces a switch in protein production in the tumor immune microenvironment and that this switch is driven primarily by changes in the CXCL5-CXCR2 axis. It also decreases antitumor immunity by modulating the chemokine/chemokine receptor signaling pathway, either through downregulating anti-tumor immune molecules or upregulating immunosuppressive molecules. Further investigations by Bishehsari et al (47) provided insights into the consequences of circadian rhythm disruption on tumor development and demonstrated that circadian rhythm disruption may promote the occurrence and development of tumors. This promotion was associated with a high permeation state, a decrease in the overall and relative abundance of CD3+ and T cells infiltrating polyps, a decrease in polyp-related density of Tregs and an increase in FOXP3+ Treg/RORgt+ Th17 ratio. These changes in immune cells under circadian rhythm disruption highlight the importance of the circadian rhythm in immune responses. The balance between proinflammatory and anti-inflammatory macrophages in the spleen and tumor is disrupted, shifting toward a more immunotolerant spectrum. The changes in immune cells facilitate immune escape and tumor progression, indicate that circadian disruption affects not only the local immune microenvironment but also peripheral immunity (68). Zeng et al (69) elucidated how circadian rhythm disorders speed up the aging and functional decline of natural killer (NK) cells in the bone marrow and spleen of mice, marked by an increase in the proportion of senescent CD27−CD11b+ cells, a reduction in functional CD27+CD11b+ cells, alterations in receptor expression and compromised immune functions, including a decrease in IFN-γ secretion and CD107a activity, leading to a decrease in NK cell numbers in the spleen and lungs, weakening of immune surveillance capabilities and a decrease in response to IL-15 due to lower expression of CD122. In the context of glioma, the effect of cancer on immunity varies under conditions of circadian rhythm disruption. In lower-grade glioma, the recruitment of immune cells increases, but their tumor-killing effect weakens; however, in glioblastoma multiforme, immune cell recruitment is inhibited (70). This variation suggests that circadian disruption can have different effects on the immune response according to the stage and type of cancer. These studies collectively showed that circadian disruption can significantly alter the body's ability to fight cancer by influencing cytokine-chemokine networks, altering immune cell populations and changing immune surveillance functions.

Genetic studies linking genes to circadian rhythms in mouse models

Genetic studies in mouse models demonstrate critical links between circadian genes and physiological functions. BMAL1 deletion disrupts circadian clock activity, altering respiratory cycle timing with time-of-day and sex-specific variations, underscoring the importance of circadian genetics in respiratory regulation (71). Strain-specific genetic differences in clock genes between C57BL/6 and BALB/c mice drive distinct cellular and behavioral adaptations to circadian disruption, highlighting genetic contributions to circadian resilience (72). Targeted disruption of vasoactive intestinal peptide (VIP) neurons in ViptTA knock-in mice impairs circadian rhythms, demonstrating the essential role of VIP signaling in maintaining central clock synchrony and behavioral rhythms (73). Similarly, deleting the Dicer gene in the SCN shortens circadian periods and reduces locomotor rhythm precision, proving microRNAs (miRNAs; miRs) are vital for robust SCN-driven oscillations (74). Loss of all mature miRNAs in the SCN shortened the circadian period length by ~37 min at the tissue level and by ~45 min at the locomotor activity level. Additionally, high-fat diets in female ICR mice (a genetically diverse outbred strain of albino mice originally developed by the Institute of Cancer Research) induce obesity, disrupt diurnal feeding patterns and dysregulate corticosterone rhythms, linking diet-induced metabolic dysfunction to circadian and endocrine disruptions through genetic or circadian pathway interactions (75). Together, these findings emphasize how genetic variations, neural circuits and external factors collectively shape circadian physiology and disease susceptibility (Table I).

Table I. Genetic studies linking genes to circadian rhythms in mouse models.

Table I.

Genetic studies linking genes to circadian rhythms in mouse models.

Gene	Mouse model	Circadian phenotype	(Refs.)
BMAL1	BMAL1 knockout	BMAL1 knockout males exhibit altered respiratory phase durations, while ventilation remains unaffected.	(71)
CLOCK	CLOCK mutant	Altered respiratory cycle timing and sex-specific metabolic phenotypes observed.	(71)
NPAS2	C57BL/6 and BALB/c	BALB/c mice adapt more rapidly to light-dark cycle shifts than C57BL/6 mice and exhibit significantly reduced Npas2 expression	(72)
	C57BL/6 vs. BALB/c	Strain-specific differences in circadian period, entrainment range, and stress resilience linked to genetic variations.	(72)
VIP neurons	VIP-deficient transgenic	VIP neuronal ablation disrupts SCN network synchronization; exogenous gene expression tools developed for studying VIP neuron roles.	(73)
Dicer	SCN-specific Dicer knockout	Loss of Dicer in the SCN reduces circadian rhythm precision and promotes ultradian rhythms under constant light.	(74)
	High-fat diet-induced obesity	Attenuated corticosterone circadian rhythms observed in obesity models.	(75)

[i] BMAL1, basic helix-loop-helix ARNT like 1; CLOCK, heterodimeric clock circadian regulator; VIP, vasoactive intestinal peptide; SCN, suprachiasmatic nucleus.

Potential of circadian clock genes as cancer biomarkers

High expression levels of the clock genes PER2 and BMAL1 are associated with good prognosis in colorectal cancer and gastric cancer, highlighting the key role of these genes in cancer progression and their lower expression is significantly associated with distant metastasis, emphasizing the importance of these genes in cancer metastasis potential (76,77). The expression of PER1 and PER2 is related to the differentiation state of the tumor and their expression decreases as the degree of tumor differentiation decreases. This relationship suggests a role for these genes in maintaining tumor differentiation, with implications for prognosis and treatment strategies (78,79). Researchers have investigated the significance of various circadian rhythm genes in cancer prognosis. High expression of CRY1 is an independent factor for metachronous metastasis, suggesting that it may serve as a predictive biomarker for future metastatic events (80). Similarly, high levels of REV-ERBβ are also an independent prognostic factor for local cancer recurrence (81). These findings highlighted the multifaceted roles these genes serve in regulating cancer progression and recurrence (82). Further emphasizing the prognostic significance of these genes, high expression of PER2 and BMAL1 was associated with improved overall and disease-free survival, whereas high CRY1 expression and low BMAL1 expression were associated with lower five-year overall and disease-free survival (76). This association provides valuable insights into the use of these genes as biomarkers for assessing patient prognosis and guiding treatment decisions. The state of clock genes and their oscillatory rhythms may be assessed to evaluate the status and effectiveness of cancer treatment. This assessment offers a promising avenue for personalized cancer therapy, where understanding the expression patterns of the circadian clock genes may guide treatment planning and prognosis estimation in the future.

Period and cancer

In analyzing polygenic, multifactorial diseases such as cancer, evidence was integrated across scales, from molecular to organismal, to reflect the current state of the field. This approach acknowledges the necessity of combining direct biochemical evidence (such as protein interaction assays) with indirect clinical correlations (such as survival analysis of circadian gene signatures) to construct testable mechanistic hypotheses (83). The PER gene family, consisting of PER1, PER2 and PER3, forms a core component of the circadian circuit (69). The protein functions as a dimer together with the clock gene CRY and PER can still complete at least one full cycle even in CRY1/2 knockout cells (84). These findings suggest that PER may independently inhibit the oscillation of the circadian rhythm, whereas CRY contributes to the continuation of these oscillations.

The intricate relationship between the expression of PER genes and the oscillations of circadian rhythms is closely intertwined with the onset, progression and treatment responses of various types of cancer (Table II). This connection is pivotal when assessing the tumor state and treatment efficacy, with the level of PER expression and changes in oscillatory rhythms serving as key indicators. Yin et al (85) reported significant alterations in the mesor (rhythm-adjusted mean), amplitude and acrophase (peak phase of the rhythm) dimensions of PER1 in oral squamous cell carcinoma. In high-grade breast cancer, the PER2 protein can be detected, but oscillation is absent, which contrasts with low-grade breast cancer, where oscillation still occurs (86,87). This pattern is also found in the transformation of oral cheek mucosal cancer, where there is a marked decrease in the median and amplitude of PER2 mRNA expression as the cancer progresses (88). The role of PER2 extends to non-small cell lung cancer, with its expression associated with the degree of differentiation and tumor-node-metastasis stage (89). Additionally, the significance of PER3 is indicated by its correlation with the stage of breast and colorectal cancer (90,91). Several studies have shown that higher levels of PER protein are associated with a significant increase in overall survival rates (77–79,92). Yang et al (93) reported a significant relationship between the restoration of PER3 and the likelihood of cancer recurrence, positioning PER genes as prognostic markers in tumor diagnostics and management. Genetic variations in PER are closely related to cancer susceptibility. Rajendran et al (94) reported a significant association between gastric cancer susceptibility and gene polymorphisms, including PER1 rs3027178 and PER2 rs934945. In soft tissue sarcoma; Benna et al (95) identified associations with PER1 rs3027178, PER2 rs934945 and rs7602358 upstream of PER2. Moreover, associations between the PER3 gene rs228729 and lung cancer and between rs2640908 and prostate cancer were reported by Couto et al and Hinoura et al (96,97). Dagmura et al (98) reported that the PER2 variable number tandem repeat polymorphism is related not only to the occurrence of cancer but also to the perineural invasion of cancer. The PER gene interacts with various cancer-related genes and pathways to influence the development of cancer (Fig. 2).

Figure 2. Mechanisms by which PER inhibits tumors. The PER gene interacts with various cancer-related genes and pathways to influence the development of cancer. miR, microRNA; PER, period circadian regulator; p53, protein 53; ALKBH5, AlkB homolog 5; m6A, N6-methyladenosine; YTHDF2, YT521-B homology domain family 2; CDKs, cyclin-dependent kinases; CKIs, CDK inhibitors; HIF1α, hypoxia-inducible factor 1α; Aldh3a1, aldehyde dehydrogenase 3 family, A member 1; KMT2D, lysine-specific methyltransferase 2D; SREBP1c, sterol regulatory element-binding protein 1c; UV, ultraviolet; MDM2, MDM2 proto-oncogene; ZNF704, zinc finger protein 704; SIN3A, SIN3 transcription regulator family member A; OCT1, POU class 2 homeobox 1; Bid, BH3-interacting domain death agonist.

Table II. Period gene family and cancer.

Table II.

Period gene family and cancer.

A, PER1
Types of cancer	Pathways of action	Results of action	(Refs.)
Oral	PER1 altered the AKT/mTOR signaling pathway.	PER1 is inhibited in oral squamous cell carcinoma and overexpression of PER1 suppresses tumor growth.	(85)
	PER1 regulates cell cycle-related genes.		(99)
	PER1 regulates the AKT/mTOR signaling pathway.		(101)
Lung	PER1 and P53 negatively regulate each other's expression and activity.	PER1 reduces the sensitivity of lung cancer cells to drug-induced apoptosis.	(102)
Cholangio-carcinoma	PER1 is regulated by miRNA-34a.	MiRNA-34a promotes the progression of cholangiocarcinoma by inhibiting the expression of PER1.	(104)
Pancreatic	ALKBH5 regulates PER1 post-transcriptional activation by demethy-lating m6A.	The absence of ALKBH5 leads to reduced activation of PER1, promoting the progression of pancreatic cancer.	(105)
Gastric	In HER2-positive gastric cancer resistant to trastuzumab, glycolysis is regulated by the BMAL1-CLOCK-PER1-HK2 axis.	Silencing PER1 enhances the therapeutic effect of trastuzumab in the treatment of gastric cancer.	(129)
B, PER2
Types of cancer	Pathways of action	Results of action	(Refs.)
Buccal mucosa carcinoma	The relative expression of PER2 mRNA in different stages of carcinogenesis was analyzed.	PER2 mRNA expression decreased with tumor progression.	(88)
Glioma	Lycium barbarum polysaccharide may reduce the expression of SREBP1c by upregulating the expression of PER2.	In glioma, PER2 expression is down-regulated, and overexpression of PER2 inhibits cancer.	(106)
	PER2 increases TP53 expression, DNA damage repair and apoptosis.		(107)
	PER2 acts on Wnt/β-catenin signaling pathway.		(108)
Oral	PER2 regulated the mRNA expression of Ki-67, MDM2, c-Myc, Bcl-2, MMP2, VEGF, p53, Bax and TIMP-2.	Oral squamous cell carcinoma cells suppress the expression of PER2 and PER2 inhibits cancer progression.	(109)
	PER2 regulates the P53/P14ARF, PIK3CA/AKT, and caspase-8 pathways.		(110)
	PER2 upregulates TP53 and inhibits EMT.		(111)
	PER2 regulates the cyclin/CDK/CKI cell cycle network		(112)
Breast	Per2 deficiency maintains mammary epithelial cells in a pre-differentiated stage.	A defect in the PER2 gene leads to underdevelopment of glands in mice.	(113)
	Hypoxia promotes the pathway of EMT by degrading PER2.	PER2 inhibits the growth and metastasis of breast cancer.	(114)
	The ZNF704/SIN3A complex inhibits PER2.		(115)
Ovarian	PER2 gene affects the PI3K/AKT signaling pathway.	PER2 inhibits ovarian tumor growth, metastasis and drug resistance.	(116)
	PER2 promoted NM23-H1 expression by inhibiting MTA-1 expression.		(117)
Cervical	PER2 affects the PI3K/AKT pathway.	PER2 overexpression inhibits tumor progression and cisplatin resistance.	(118)
Thyroid	PER2 can induce AP-1 activity by activating the JNK/MAPK signaling pathway.	Reduced PER2 expression promotes cancer cell proliferation.	(119)
Lung	KMT2D deletion reduces PER2 expression, thereby regulating multiple glycolysis genes.	PER2 inhibits glycolysis and blocks tumorigenesis.	(120)
Kidney	HIF1α increases the amplitude of PER2 oscillations.	PER2 inhibits proliferation of renal cell carcinoma.	(122)
C, PER3
Types of cancer	Pathways of action	Results of action	(Refs.)
Breast	PER3 affects the MEK/ERK signaling pathway.	PER3 inhibits breast cancer.	(90)
Colorectal	PER3 affects Notch and β-catenin signaling pathways.	The expression of PER3 is decreased in colorectal cancer. Overexpression of PER3 can inhibit the proliferation, invasion and drug resistance of colorectal cancer cells.	(91)
	PER3 is targeted by miRNA-103.		(126)
	circMETTL3/miRNA-107 regulates colorectal cancer through PER3.		(127)

[i] PER, period circadian regulator; ALKBH, AlkB homolog 1, histone H2A dioxygenase; CLOCK, heterodimeric clock circadian regulator; SREBP1c, sterol regulatory element binding transcription factor 1; TIMP-2, TIMP metallopeptidase inhibitor 2; BMAL1, basic helix-loop-helix ARNT like 1; EMT, epithelial-mesenchymal transition; SCN, suprachiasmatic nucleus; ZNF704, zinc finger protein 704; SIN3A, SIN3 transcription regulator family member A; MTA-1, metastasis associated 1; HIF1α, hypoxia-inducible factor 1α; miRNA, microRNA; KMT2D, lysine-specific methyltransferase 2D.

PER1 and cancer

Yin et al (85) found that PER1 exhibits abnormal changes in three key dimensions: the mesor, amplitude and acrophase dimensions. This finding is important for understanding the role of genes in cancer. These changes in PER1 lead to a cascading effect in the clock gene network. The downregulation of PER1 triggers the upregulation of genes such as PER3, RORA and REV-ERBα while simultaneously leading to the downregulation of PER2, CRY1, CRY2 and NPAS2 (99). This pattern of alteration of gene expression indicates a fundamental difference between cancerous and normal cells, significantly affecting tumor growth, proliferation, metastasis and treatment responses. By further investigating the effects of PER1, direct knockout studies have demonstrated notable outcomes. The removal of PER1 decreases apoptosis and increases cell proliferation, ultimately promoting tumor formation (99). The effect of PER1 extends to the cell cycle, a key aspect disrupted in cancer. Silencing the PER1 gene in oral squamous cell carcinoma significantly affects the cyclin-CDK-CKI cell cycle molecular regulatory network, particularly affecting the G1/S checkpoint (100). This disruption is evident in the altered levels of several cell cycle-related genes. The results of qRT-PCR and Western blotting analyses have shown an increase in the levels of cyclin D1, cyclin E, cyclin B1, CDK1 and Wee1, coupled with a decrease in the levels of p53, Cyclin A2, p16, p21 and cdc25 (100). Yang et al (101) contributed to the understanding of the role of PER1 in oral squamous cell carcinoma. The authors found that overexpressing PER1 promotes autophagy and apoptosis while inhibiting cell proliferation and the AKT/mTOR pathway and further demonstrated that PER1, through its effects on AKT activators and autophagy inhibitors, can inhibit autophagy-mediated apoptosis and promote cell proliferation in an AKT/mTOR pathway-dependent manner (101).

A study by Bellet et al (102) on lung cancer provided significant insights into the intricate relationship between the circadian clock gene PER1 and the tumor suppressor factor P53. The authors reported that PER1 can affect the stability and transcriptional activity of P53. PER1 reduces the stability and transcriptional activity of P53. This finding is important because P53 suppresses tumor development by inducing cell cycle arrest, apoptosis, cellular senescence and DNA repair (103). A reduction in P53 activity due to PER1 can decrease the efficacy of these tumor-suppressing actions, thereby affecting the sensitivity of cancer cells to treatment. Conversely, P53 can inhibit the binding of CLOCK/BMAL1 to the PER1 promoter. CLOCK and BMAL1 are core components of the molecular circadian clock and their binding to the PER1 promoter is essential for regulating PER1 expression. The inhibition of this binding by P53 suggests a feedback mechanism in which P53 can regulate the expression of PER1, possibly to maintain cellular homeostasis and prevent abnormal growth of cells (88).

In the context of cholangiocarcinoma, investigation on the effect of PER1 on the cyclin-CDK-CKI cell cycle molecular network has been conducted. Overexpressing the PER1 gene results in a considerable reduction in G2/M phase blockade and an increase in apoptosis in cholangiocarcinoma cells, which highlights the role of PER1 in regulating critical phases of the cell cycle and promoting cancer cell death (104). In pancreatic cancer, the role of PER1 has been investigated in the context of the ATM pathway. Overexpressing PER1 affects the cell cycle molecular network through this pathway and this overexpression helps restore molecules associated with the ATM-dependent pathway, including p-ATM, p-CHK2, pCDC25C, p-P53, P21 and p-CDK1 (105). Reactivating the ATM-CHK2-P53/CDC25C signaling pathway results in the inhibition of cell growth, highlighting that PER1 serves a key role in hindering the progression of pancreatic cancer.

PER2 and cancer

In a study involving the Lycium barbarum glycopeptide, researchers reported that its extract, known as LbGP, can upregulate the expression of PER2 through the PKA-CREB pathway (106). An increase in PER2 expression subsequently inhibits the PI3K/AKT/mTOR pathway, which is key for regulating various cellular processes, including cell proliferation (106). Due to this inhibition, sterol regulatory element binding transcription factor 1 (SREBP1c), a key regulator of lipid synthesis, is negatively affected and the downregulation of SREBP1c reduces lipid synthesis and cell proliferation in glioblastoma, indicating that SREBP1c may be a potential therapeutic target (106). Regarding the tumor suppressor gene P53, which serves a role in cell cycle arrest, apoptosis and aging, Zhanfeng et al (107) reported that PER2 regulates apoptosis in glioma cells through the ATM-P53 pathway. PER2 promotes the expression of ATM and P53 while inhibiting the expression of c-myc and MDM2 proto-oncogene (MDM2) and this activity of PER2 is significant during DNA damage and p53-mediated apoptosis in glioma cells (107). Ma et al (108) reported that PER2 can downregulate the Wnt/β-catenin signaling pathway, which regulates the stemness of glioma stem cells. PER2 overexpression results in cell cycle arrest at the G0/G1 phase, reducing the stemness, self-renewal ability and migration of glioma stem cells. These findings suggest that PER2 affects the behavior and characteristics of glioma stem cells, influencing their potential for proliferation and invasion.

The function of the PER2 gene is closely related to its effect on P53 (109). Following this line of investigation, researchers found that attenuating PER2 expression leads to the upregulation of MDM2 mRNA (109). This is notable because P14ARF mitigates the ubiquitination and subsequent degradation of P53 via MDM2, ultimately increasing the concentration of functional P53 in cells, a key factor in tumor suppression (110). Xiong et al (110) reported that PER2 affects the PI3K/AKT pathway, a key regulator of tumor cell proliferation, invasion and metastasis. The lack of PER2 suppresses PTEN expression, weakening the negative control of the PI3K/AKT pathway, thereby activating the pathway. PER2 may also affect the PI3K/AKT pathway through its interaction with the P110 subunit encoded by PIK3CA (110). Guo et al (111) reported that PER2 not only increases the expression of the TP53 gene but also impedes EMT. The authors reported that the downregulated expression and subcellular localization of PER2 in oral squamous cell carcinoma tissues and cells leads to the activation of EMT transcription genes such as TWIST1/2, ZEB1/2 and MMP1, thereby enhancing the invasiveness of the tumor (111). Additionally, the cell cycle network is disrupted in oral cancer. This disruption is characterized by an increase in mRNA levels of cyclins (A2, B1 and D1) and CDKs (CDK4 andCDK6), whereas the mRNA levels of P53, P16 and P21 decrease and cancer cells exhibit a significant reduction in G1/G0 phase cells, increase in cell proliferation and decrease in apoptosis (112). Finally, knocking down PER2 increases the expression of tumor-related genes such as Ki-67, MDM2, c-Myc, Bcl-2, MMP2 and VEGF, decreases the expression of p53, Bax and TIMP metallopeptidase inhibitor 2, increases cancer cell proliferation, migration and invasion and reduces the number of apoptotic and G1/G0 phase cells (109).

McQueen et al (113) provided insights into the role of PER2 in cancer biology, particularly concerning EMT. The researchers found that PER2 serves a key role in suppressing the expression of the EMT-related transcription factor SNAI2. To further assess the significance of PER2 deficiency, the authors reported that in PER2−/− mice, mammary epithelial cells could not fully mature and remained in a precursor state of luminal and myoepithelial mammary cell types (113). This hindrance in cell maturation due to the lack of PER2 is an important finding, as it suggests a mechanism by which PER2 influences cancer progression. Alterations in EMT-related pathways due to PER2 suppression enhance cancer cell stemness, along with their migration and invasion ability. This enhancement is a key factor in the aggressiveness and metastatic potential of cancer cells (113). Hwang-Verslues et al (114) demonstrated that PER2 acts as a corepressor and interacts with the POU class 2 homeobox 1 (OCT1) gene, which encodes a transcription factor protein that serves a key role in cell differentiation and maturation. PER2 then recruits a complex containing EZH2, SUZ12 polycomb repressive complex 2 subunit and histone deacetylase 2 (HDAC2), which may convert the usually active OCT1 sites into repressive sites through HDAC2-mediated histone deacetylation, thereby inhibiting EMT. Hwang-Verslues et al (114) also reported a link between EMT activation and hypoxic conditions, in which the PER2 protein is degraded, disrupting the connection between the OCT1 site and the repressor complex and this disruption leads to the activation of EMT gene expression. Finally, the zinc finger protein 704 (ZNF704)/SIN3 transcription regulator family member A complex, suppresses PER2 expression and this suppression extends the circadian clock cycle and reduces its amplitude (115). This intricate network of interactions and regulatory mechanisms involving PER2 highlights its potential as a target for therapeutic interventions in cancer treatment.

Wang et al (116) demonstrated a strong link between the decreased protein level of PER2 in various types of cancer and the methylation of CpG islands, suggesting an epigenetic regulatory mechanism. The PI3K/AKT signaling pathway is a downstream signal transduction pathway involving various factors. The PI3K/AKT signaling pathway participates in antiapoptotic activity and promotes cell proliferation, migration and carcinogenesis (101). Wang et al (117) reported that overexpression of PER2 inhibits the activation of AKT and further induces the expression of nm23-H1, subsequently suppressing the expression of metastasis-associated protein 1, which may be related to the metastatic potential of cancer cells, thereby inhibiting the proliferation, angiogenesis, invasion and metastasis of tumor cells. These findings were also found in ovarian cancer research, where PER2 was shown to regulate critical elements of the cell cycle network, including cyclin E and c-myc; the absence of PER2 was found to disrupt this network, impair DNA damage repair, reduce the efficiency of the cell response to DNA damage through cycle checkpoints and ultimately lead to the deterioration of the health of cells (116). Additionally, Wang et al (116,118) studied treatment resistance in cervical and ovarian cancer and found that overexpression of PER2 affects the PI3K/AKT pathway, a key factor influencing the resistance of these types of cancer to chemotherapy.

Lee et al (119) studied thyroid cancer and found a significant disruption in the aging-related PER2 gene, which is characterized by a linear pattern in circadian oscillation and a substantial reduction in protein levels. They also found that when the circadian clock gene PER2 is knocked down, it triggers an increase in AP-1 activity, and this activation occurs through the JNK signaling pathway, leading to an increase in cell proliferation (119).

Alam et al (120) reported the key role of lysine-specific methyltransferase 2D (KMT2D), an epigenetic modifier, in the context of lung cancer; KMT2D is one of the most frequently inactivated modifiers in this type of cancer and therefore, its connection to PER2 is particularly noteworthy (105). The authors reported that the absence of KMT2D leads to a reduction in PER2 expression, which results in the upregulation of various glycolytic genes, including ENO1, PGK1, PGAM1, LDHA, GAPDH and CDK1 (120). The upregulation of these genes strongly promotes tumorigenesis, as indicated by their findings.

The role of hypoxia-inducible factor (HIF) in renal cell carcinoma is a significant area of interest in cancer research and HIF1α serves a key role in the cellular response to hypoxia by regulating various genes involved in key processes such as angiogenesis, metabolism and cell survival (121). HIF1α increases the amplitude of PER2 oscillation by directly binding to the HIF-binding site on the PER2 promoter, thereby altering PER2 activity (122). This increase in transcriptional activity inhibits tumor proliferation, suggesting that targeting the HIF1α-PER2 pathway may be a viable strategy for slowing or inhibiting the progression of renal cell carcinoma.

HCC has a significant global health impact and is the third leading cause of cancer-related death worldwide. HCC pathogenesis involves complex interactions between viral infections (such as hepatitis B/C viruses) and dietary/lifestyle factors (123). Several studies have highlighted the role of circadian rhythm disruption and dietary dysregulation in the development of HCC, particularly among populations with irregular lifestyles, such as night-shift workers (124,125). The hepatic physiology follows a daily rhythm, driven by clock genes that control the expression of several proteins involved in distinct metabolic pathways. Alteration of the liver clock results in metabolic disorders, such as non-alcoholic fatty liver diseases (NAFLD) and impaired glucose metabolism, which can trigger the activation of oncogenic pathways, inducing spontaneous HCC.

Downregulation of PER2 in HCC tissues is correlated with suppressed p53 expression and overexpression of c-Myc, potentially promoting tumor progression (98,99). Environmental disruption of circadian rhythms (such as jet lag) accelerates hepatocarcinogenesis in mice, accompanied by altered PER2 rhythmicity in liver and tumor tissues (98). PER2 loss of function may exacerbate genomic instability and inflammation, which are key drivers of HCC initiation (99). While these findings highlight the tumor-suppressive role of PER2 in HCC, the mechanism by which PER-mediated circadian disturbances directly contribute to HCC remains undetermined.

PER3 and cancer

Hong et al (108) and Zhang et al (91) provided significant insights into the role of PER3 in colorectal cancer, highlighting its potential as a target for therapeutic intervention. Hong et al (108) studied colorectal cancer and found that PER3 overexpression significantly reduces cancer cell proliferation and invasion while enhancing their apoptosis, largely through the effect of PER3 on the mitochondrial apoptosis pathway and the cell cycle network. A key discovery of the study involves the Bcl-2 family, which is key to the mitochondrial pathway. The authors noted an increase in Bid and a decrease in Bcl2 expression, highlighting the role of PER3 in promoting apoptotic pathways in cancer cells. It was also found that miR-103 targets PER3 by binding to its 3′ UTR, influencing apoptosis-related genes in the p53 pathway and altering the expression of cell cycle molecules such as cyclin B1 and CDC2 (126). Zhang et al (127) reported that PER3 is regulated by RUNX3, which activates the transcription of circMETTL3 by binding to the METTL3 promoter and this transcription then directly targets PER3 with miR-107 to regulate cancer cell proliferation and invasion. Additionally, PER3 has a strong effect on the stemness of colorectal cancer stem cells and suppressing the Notch or β-catenin signaling pathways may decrease chemotherapy resistance and self-renewal in these cells (91). PER3 overexpression decreases the levels of stemness markers such as Notch1, Jagged1, β-catenin, c-Myc and LGR5 in colorectal cancer stem cells, which is correlated with the inhibition of the Notch and β-catenin pathways; these pathways are vital for maintaining stemness and chemotherapy resistance in these cells (91).

Liu et al (90) provided valuable insights into the role of PER3 in breast cancer, particularly concerning the MEK/ERK signaling pathway, which serves a key role in cell proliferation, invasion and metastasis. Liu et al (90) demonstrated that silencing PER3 in breast cancer cells significantly inhibits the MEK/ERK signaling pathway, as shown by a decrease in the levels of p-MEK and p-ERK1/2 proteins. This pathway serves a vital role in regulating cell growth and survival, indicating that PER3 silencing substantially affects the ability of cancer cells to proliferate, invade and metastasize. The authors also demonstrated the potential of modulating the effects of PER3 on the MEK/ERK pathway via specific inhibitors and activators, such as PD98059, an inhibitor of MEK and TPA, an activator, in cells with altered PER3 expression (90). This approach suggests that manipulating PER3 expression, along with the targeted use of MEK/ERK pathway inhibitors or activators, can offer an effective strategy to control the progression of breast cancer.

PER serves an important role in cancer development and significantly affects the behavior of cancer cells. Alterations in PER gene expression affect cell proliferation, apoptosis and metastasis across various types of cancer cells. In oral cancer, breast cancer, ovarian cancer, cervical cancer, thyroid and glioblastoma cells, silencing PER2 promotes cancer cell proliferation, reduces apoptosis and increases in vivo metastasis, invasion and tumorigenesis (106,108,109,111,114,117–119). In contrast to the suppressive effect on p53 observed with PER1 overexpression in lung cancer (100,102), PER2 overexpression leads to an increase in p53 expression (111). Moreover, PER2 overexpression in glioblastoma inhibits lipid synthesis (106) and induces morphological changes in cervical cancer cells (118), thereby suppressing cancer cell proliferation. In breast and colorectal cancer cells, altering silenced PER3 expression increases proliferation, invasion and metastatic capabilities and decreases apoptosis (90,126,127). Additionally, overexpressing PER1 increases autophagy in cancer cells (101) and reciprocal negative regulation between PER1 and p53 gene expression and activity (100,102). PER2 also affects cell autophagy, potentially related to its interference with the PI3K/PKB pathway (104). Overexpressing PER1 inhibits the cell cycle network, EMT and angiogenesis capabilities in cholangiocarcinoma (104). The PER2 gene also affects the cell cycle cyclin/CDK/CKI network, angiogenesis, EMT and glycolysis, which are closely associated with its anticancer effects (108,109,111,112,114,120,128).

The occurrence and development of tumors strongly influence the circadian rhythm and expression of PER genes. In lung, gastric, oral and pancreatic cancer, a weakened circadian rhythm and reduced gene expression of PER1 were found in patients, with a decrease in PER1 expression as the tumor progresses through various stages (79,85,89,105). Low expression of PER1 in patients with pancreatic cancer is associated with shorter survival (105). Patients with higher levels of PER expression (1–3) in patients with lung cancer have higher survival rates compared with those with lower levels of PER expression (89). Similarly, weakened circadian rhythms and reduced gene expression of PER2 occur in lung, breast, oral and ovarian cancer, cholangiocarcinoma and glioma stem cells, with PER2 expression decreasing as the tumor progresses in stage (85,89,90,104,108,114,117). In high-grade ovarian cancer and most renal cancer cells, neither the circadian rhythm nor the protein level of PER2 can be detected (117,122). Additionally, a weakened circadian rhythm and a decrease in the expression of the PER3 gene were found in lung, breast and colorectal cancer and leukemia, with a decrease in the expression of the PER3 gene as the tumor progresses (89,90,93,114,126,127). Furthermore, recovery of PER3 expression was observed in both patients with AML and those with ALL who achieved remission but not in patients who relapsed after treatment (93).

Overall, the experimental evidence suggests that PER potentially inhibits cancer progression. However, Bellet et al (102) introduced a nuanced perspective, reporting that in mice with xenografted lung cancer cells, PER1 can reduce the sensitivity of cancer cells to drug-induced apoptosis. This counterintuitive finding indicates that while PER1 activation might decrease the effectiveness of certain cancer therapies, it may benefit normal cells by mitigating the cytotoxic effects of these drugs. In the context of gastric cancer, Wang et al (129) investigated the therapeutic potential of PER1, reporting that PER1 can reverse the drug resistance of cancer cells, specifically regulating HK2-dependent trastuzumab resistance through interaction with PPARG and that this specific form of drug resistance can be reversed by silencing PER1 or using metformin to degrade the PER1 protein and inhibit glycolysis. The association between PER2 and cancer drug resistance represents a significant area of research. Wang et al (101,103) reported that overexpressing PER2 can modulate drug resistance factors through the PI3K/AKT pathway. This modulation decreases the level of multidrug-resistant proteins, which are major hurdles in the treatment of various types of cancer, including cervical and ovarian cancer (116,118). By inhibiting drug resistance, PER2 overexpression enhances the effectiveness of chemotherapy, offering a promising avenue for improving cancer treatment outcomes (118,130). Katumune et al (131) demonstrated that PER2 can recruit HDACs to the promoter region of aldehyde dehydrogenase 3 family member A1 (ALDH3A1), reducing the acetylation level of H3K9 and acting as an inhibitor of ALDH3A1 expression. However, mutated PER2 could not recruit HDACs, leading to an increase in ALDH3A1 expression and ultimately causing cells to develop resistance to chemotherapeutic drugs. In the context of lung cancer, paclitaxel nanoparticles exhibited the most effective antitumor activity and reduced liver damage 15 h after light onset through the upregulation of PER2 expression to induce apoptosis in vivo and in vitro, suggesting a chronotherapy strategy to optimize drug timing, potentially improving efficacy and reducing side effects in clinical settings (132). Additionally, the relevance of PER2 in the context of X-ray treatment in glioma cell studies further highlights its role in various cancer treatments (107). Notably, PER3 enhances the inhibitory effect of 5-fluorouracil (5-FU) on tumor stem cells, which is a significant development given that 5-FU is a widely used chemotherapeutic drug (91). The enhancement of the effectiveness of 5-FU by PER3 is significant for targeting tumor stem cells, which serve an important role in chemotherapy resistance and cancer recurrence, suggesting that PER3 targeting may be a viable strategy to improve treatment outcomes and address the challenges posed by tumor stem cells in cancer therapy. The correlation between PER3 and posttreatment side effects, identified via polygenic risk score analysis, is a significant aspect of its role in cancer therapy (133). The promising discovery that altering treatment timing according to different PER3 genotypes can decrease side effects highlights the potential of personalized medicine, where treatment is customized based on individual genetic profiles to optimize efficacy and reduce adverse effects. Additionally, PER3 inhibits the resistance and self-renewal of colorectal cancer stem cells, which is associated with the inhibition of the Notch and β-catenin signaling pathways, highlighting its therapeutic potential (91). These pathways are essential for maintaining cancer cell stemness and drug resistance and the role of PER3 in inhibiting these pathways indicates that it may hold the key to addressing major challenges in cancer treatment. A clinical trial by Yang et al (93) demonstrated the ability of PER3 to serve as a biomarker for treatment effectiveness in leukemia, with the restoration of PER3 expression in acute myeloid and acute lymphoblastic leukemia patients who experienced remission but not in those who relapsed, indicating that PER3 levels might reflect the response of patients to treatment. These findings highlight the complex and contradictory relationship between PER and cancer drug resistance, which may be attributed to the extensive and complex interactions of the downstream targets of the PER gene in different genetic backgrounds.

Conclusions

The current landscape of circadian-cancer research is characterized by fragmented yet convergent evidence. While definitive causal links remain scarce for numerous pathways (such as circadian control of epigenetic reprogramming), the present review underscored the urgency of bridging in vitro findings with in vivo validation tools to unravel context-dependent mechanisms. The circadian clock is extensively present in the human body, strongly influencing internal functions and helping the body adapt to external environmental changes, serving a key role in regulating life activities. In modern society, numerous individuals experience circadian rhythm disorders for various reasons, such as shift work, chronic jet lag, high fat intake and abnormal sleep patterns. Circadian rhythm disruption is an independent risk factor for cancer and the disruption of circadian rhythm genes is closely related to the occurrence, development and treatment of cancer. The members of the PER family, as core components of the circadian clock cycle, serve vital roles in maintaining these rhythms. Dysregulation of PER genes is closely associated with the occurrence, development and treatment of various types of cancer, as PER dysregulation affects key regulatory pathways related to cancer, including those governing the cell cycle, apoptosis, DNA repair, metabolism and stem cell maintenance. These pathways are important for tumor development and progression, making the PER family a key focus in cancer research. The understanding of the mechanisms by which PER genes regulate cancer is currently evolving. Further in-depth research is needed to decipher these complex interactions. This includes understanding the tissue-specific expression of PER genes, as the role and rhythm of PER expression can vary significantly between different tissues.

Exploring the potential of lifestyle changes to restore normal circadian rhythms and consequently, PER expression is another promising area of research. Such interventions may reduce cancer incidence and improve patient outcomes. Additionally, aligning the timing of therapeutic drugs with PER expression and biological rhythms offers an effective approach for reducing side effects and enhancing treatment efficacy. Continued research on the interactions between PER genes and other rhythmically secreted hormones is also necessary, as this may provide further insights into the systemic nature of circadian regulation and its effect on cancer. In conclusion, research on the circadian clock and clock genes such as PER is not just an academic pursuit but has real-world implications for cancer prevention, treatment and the quality of life of patients. Future research in this field holds the potential to revolutionize the current understanding of cancer development and progression and open new avenues for more effective cancer management.

Acknowledgements

Not applicable.

Funding

The present study was funded by the Science and Technology Program of Binzhou Medical College (grant no. BY2017KJ01).

Availability of data and materials

Not applicable.

Authors' contributions

PG designed the study. WX, XF and PG obtained data and drafted the manuscript. QG, YW and HZ helped design the studies and prepare the manuscript. YC drew the figures and tables. The manuscript was critically reviewed by YH, PG and YC. Data authentication is not applicable. All authors have read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patients consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References