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.

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.

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.