Similar articles

Abstract: The circadian clock is a highly conserved timekeeping system in organisms, which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression. Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies. Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues, primarily manifested as a dysfunction of core clock components (particularly circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1)) and the widespread dysregulation of their downstream target genes. Notably, CLOCK demonstrates non-canonical oncogenic functions, including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways. This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1, encompassing multidimensional effects such as cell cycle control, DNA damage response, metabolic reprogramming, and tumor microenvironment (TME) remodeling. Regarding the therapeutic strategies, we focus on cutting-edge approaches such as chrononutritional interventions, chronopharmacological modulation, and treatment regimen optimization, along with a discussion of future perspectives. The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology, particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.

昼夜节律基因CLOCK与BMAL1在癌症中的作用：机制解析与治疗策略

[1]AlhopuroP, BjörklundM, SammalkorpiH, et al., 2010. Mutations in the circadian gene CLOCK in colorectal cancer. Mol Cancer Res, 8(7):952-960.

[2]Amiama-RoigA, Verdugo-SivianesEM, CarneroA, et al., 2022. Chronotherapy: circadian rhythms and their influence in cancer therapy. Cancers, 14(20):5071.

[3]BoivinDB, BoudreauP, 2014. Impacts of shift work on sleep and circadian rhythms. Pathol Biol, 62(5):292-301.

[4]BurgermeisterE, BattaglinF, EladlyF, et al., 2019. Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A. eBioMedicine, 45:139-154.

[5]ChanP, NagaiY, WuQL, et al., 2025. Advancing clinical response against glioblastoma: evaluating SHP1705 CRY2 activator efficacy in preclinical models and safety in phase I trials. Neuro-Oncol, 27(7):1772-1786.

[6]ChenPW, HsuWH, ChangA, et al., 2020. Circadian regulator CLOCK recruits immune-suppressive microglia into the GBM tumor microenvironment. Cancer Discov, 10(3):371-381.

[7]ChoH, ZhaoX, HatoriM, et al., 2012. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature, 485(7396):123-127.

[8]Cotta-RamusinoC, McDonaldER III, HurovK, et al., 2011. A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science, 332(6035):1313-1317.

[9]CurtisAM, BelletMM, Sassone-CorsiP, et al., 2014. Circadian clock proteins and immunity. Immunity, 40(2):178-186.

[10]DamatoAR, LuoJQ, KatumbaRGN, et al., 2021. Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study. Neuro-Oncol Adv, 3(1):vdab041.

[11]DongZ, ZhangGX, QuM, et al., 2019. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov, 9(11):1556-1573.

[12]DorukYU, YarparvarD, AkyelYK, et al., 2020. A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude. J Biol Chem, 295(11):3518-3531.

[13]DuongHA, RoblesMS, KnuttiD, et al., 2011. A molecular mechanism for circadian clock negative feedback. Science, 332(6036):1436-1439.

[14]ElhananiO, Ben-UriR, KerenL, 2023. Spatial profiling technologies illuminate the tumor microenvironment. Cancer Cell, 41(3):404-420.

[15]FagianiF, di MarinoD, RomagnoliA, et al., 2022. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther, 7:41.

[16]Fang GF, Chen QY, Li JL,et al., 2024 The diurnal transcriptome reveals the reprogramming of lung adenocarcinoma cells under a time-restricted feeding-mimicking regimen. J Nutr, 154(2):354-368.

[17]FarshadiE, YanJ, LeclereP, et al., 2019. The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1. Cell Cycle, 18(1):16-33.

[18]FortinBM, PfeifferSM, Insua-RodríguezJ, et al., 2024. Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade. Nat Immunol, 25(7):1257-1269.

[19]FortinBM, MahieuAL, FellowsRC, et al., 2025. The diverse roles of the circadian clock in cancer. Nat Cancer, 6(5):753-767.

[20]FuhrL, El-AthmanR, ScrimaR, et al., 2018. The circadian clock regulates metabolic phenotype rewiring via HKDC1 and modulates tumor progression and drug response in colorectal cancer. eBioMedicine, 33:105-121.

[21]GaucherJ, MontellierE, Sassone-CorsiP, 2018. Molecular cogs: interplay between circadian clock and cell cycle. Trends Cell Biol, 28(5):368-379.

[22]GotohT, Vila-CaballerM, SantosCS, et al., 2014. The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells. Mol Biol Cell, 25(19):3081-3093.

[23]GrabeS, AnanthasubramaniamB, HerzelH, 2024. Quantification of circadian rhythms in mammalian lung tissue snapshot data. Sci Rep, 14:16238.

[24]HanZY, ZhangC, AnJX, et al., 2025. Directly evolved nanovaccines modulate disrupted circadian rhythm and enhance cancer immunotherapy. Adv Mater, 37(34):2502602.

[25]HanahanD, 2022. Hallmarks of cancer: new dimensions. Cancer Discov, 12(1):31-46.

[26]HeBK, NoharaK, ParkN, et al., 2016. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab, 23(4):610-621.

[27]HuangLH, HuangCY, LiuYW, et al., 2024. Circadian rhythm disruption in hepatocellular carcinoma investigated by integrated analysis of bulk and single-cell RNA sequencing data. Int J Mol Sci, 25(11):5748.

[28]HuangN, ChelliahY, ShanYL, et al., 2012. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science, 337(6091):189-194.

[29]JiangWL, ZhaoSL, JiangXH, et al., 2016. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett, 371(2):314-325.

[30]KamalIR, El-AttySMA, El-ZoghdySF, et al., 2025. Intelligent deep learning model for targeted cancer drug delivery. Sci Rep, 15:19068.

[31]KiesslingS, Beaulieu-LarocheL, BlumID, et al., 2017. Enhancing circadian clock function in cancer cells inhibits tumor growth. BMC Biol, 15:13.

[32]KimDW, MayerC, LeeMP, et al., 2023. Efficient assessment of real-world dynamics of circadian rhythms in heart rate and body temperature from wearable data. J Roy Soc Interface, 20(205):20230030.

[33]LeungC, GérardC, GonzeD, 2023. Modeling the circadian control of the cell cycle and its consequences for cancer chronotherapy. Biology, 12(4):612.

[34]LéviFA, OkyarA, HadadiE, et al., 2024. Circadian regulation of drug responses: toward sex-specific and personalized chronotherapy. Annu Rev Pharmacol Toxicol, 64:89-114.

[35]LiMD, 2022. Clock-modulated checkpoints in time-restricted eating. Trends Mol Med, 28(1):25-35.

[36]LiuJL, XuX, RixiatiY, et al., 2024. Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells. Cell Metab, 36(6):1320-1334.e9.

[37]LiuT, WangZ, YeLG, et al., 2023. Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth. Nat Cell Biol, 25(2):273-284.

[38]LongoVD, PandaS, 2016. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab, 23(6):1048-1059.

[39]MaYR, RenX, PatelN, et al., 2020. Nobiletin, a citrus polymethoxyflavone, enhances the effects of bicalutamide on prostate cancer cells via down regulation of NF-κB, STAT3, and ERK activation. RSC Adv, 10(17):10254-10262.

[40]MikiT, MatsumotoT, ZhaoZY, et al., 2013. p53 regulates Period2 expression and the circadian clock. Nat Commun, 4:2444.

[41]MureLS, LeHD, BenegiamoG, et al., 2018. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science, 359(6381):eaao0318.

[42]NegriniS, GorgoulisVG, HalazonetisTD, 2010. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol, 11(3):220-228.

[43]NguyenKD, FentressSJ, QiuYF, et al., 2013. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C^hi inflammatory monocytes. Science, 341(6153):1483-1488.

[44]Ortega-CamposSM, Verdugo-SivianesEM, Amiama-RoigA, et al., 2023. Interactions of circadian clock genes with the hallmarks of cancer. Biochim Biophys Acta Rev Cancer, 1878(3):188900.

[45]PangLZ, DuntermanM, XuanWJ, et al., 2023. Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma. Cell Rep, 42(2):112127.

[46]PapagiannakopoulosT, BauerMR, DavidsonSM, et al., 2016. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab, 24(2):324-331.

[47]PatkeA, YoungMW, AxelrodS, 2020. Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol, 21(2):67-84.

[48]PavlovaNN, ThompsonCB, 2016. The emerging hallmarks of cancer metabolism. Cell Metab, 23(1):27-47.

[49]PengF, LuJX, SuKY, et al., 2024. Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis. Cell Metab, 36(7):1598-1618.e11.

[50]PuH, BaileyLC, BauerLG, et al., 2025. Pharmacological targeting of BMAL1 modulates circadian and immune pathways. Nat Chem Biol, 21(5):736-745.

[51]QiGY, GuoR, TianHY, et al., 2018. Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids, 1863(6):549-562.

[52]QuM, ZhangGX, QuH, et al., 2023. Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle. Proc Natl Acad Sci USA, 120(2):e2214829120.

[53]QuailDF, JoyceJA, 2013. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 19(11):1423-1437.

[54]QueirozJDN, MacedoRCO, TinsleyGM, et al., 2021. Time-restricted eating and circadian rhythms: the biological clock is ticking. Crit Rev Food Sci Nutr, 61(17):2863-2875.

[55]RippergerJA, SchiblerU, 2006. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet, 38(3):369-374.

[56]SancarA, van GelderRN, 2021. Clocks, cancer, and chronochemotherapy. Science, 371(6524):eabb0738.

[57]SancarA, Lindsey-BoltzLA, KangTH, et al., 2010. Circadian clock control of the cellular response to DNA damage. FEBS Lett, 584(12):2618-2625.

[58]SchraderLA, Ronnekleiv-KellySM, HogeneschJB, et al., 2024. Circadian disruption, clock genes, and metabolic health. J Clin Invest, 134(14):e170998.

[59]ShiD, FangGF, ChenQY, et al., 2023. Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism. BMC Med, 21:417.

[60]SlatEA, SponagelJ, MarpeganL, et al., 2017. Cell-intrinsic, Bmal1-dependent circadian regulation of temozolomide sensitivity in glioblastoma. J Biol Rhythms, 32(2):121-129.

[61]SulliG, ManoogianENC, TaubPR, et al., 2018. Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases. Trends Pharmacol Sci, 39(9):812-827.

[62]Terzibasi-TozziniE, Martinez-NicolasA, Lucas-SánchezA, 2017. The clock is ticking. Ageing of the circadian system: from physiology to cell cycle. Semin Cell Dev Biol, 70:164-176.

[63]WangC, ZengQ, GülZM, et al., 2024. Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy. Cell, 187(11):2690-2702.e17.

[64]WangYP, QianRZ, SunN, et al., 2015. Circadian gene hClock enhances proliferation and inhibits apoptosis of human colorectal carcinoma cells in vitro and in vivo. Mol Med Rep, 11(6):4204-4210.

[65]WangYP, SunN, LuC, et al., 2017. Upregulation of circadian gene ‘hClock’ contribution to metastasis of colorectal cancer. Int J Oncol, 50(6):2191-2199.

[66]WangZ, MaLN, MengY, et al., 2024. The interplay of the circadian clock and metabolic tumorigenesis. Trends Cell Biol, 34(9):742-755.

[67]WeiT, ChengY, GeJR, et al., 2025. The pro-apoptotic effect of glucose restriction in NSCLC via AMPK-regulated circadian clock gene Bmal1. Cancer Sci, 116(8):2101-2112.

[68]WuDL, RastinejadF, 2017. Structural characterization of mammalian bHLH-PAS transcription factors. Curr Opin Struct Biol, 43:1-9.

[69]WuDL, SuXY, PotluriN, et al., 2016. NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. eLife, 5:e18790.

[70]WuYC, TaoBR, ZhangTY, et al., 2019. Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion. Front Immunol, 10:2451.

[71]XuDQ, ShaoF, BianXL, et al., 2021. The evolving landscape of noncanonical functions of metabolic enzymes in cancer and other pathologies. Cell Metab, 33(1):33-50.

[72]XuanWJ, KhanF, JamesCD, et al., 2021. Circadian regulation of cancer cell and tumor microenvironment crosstalk. Trends Cell Biol, 31(11):940-950.

[73]XuanWJ, HsuWH, KhanF, et al., 2022. Circadian regulator CLOCK drives immunosuppression in glioblastoma. Cancer Immunol Res, 10(6):770-784.

[74]YipHYK, PapaA, 2021. Signaling pathways in cancer: therapeutic targets, combinatorial treatments, and new developments. Cells, 10(3):659.

[75]YooSH, MohawkJA, SiepkaSM, et al., 2013. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell, 152(5):1091-1105.

[76]ZengYE, GuoZC, WuMQ, et al., 2024. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell Death Discov, 10:199.

[77]ZengZL, LuoHY, YangJ, et al., 2014. Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer. Clin Cancer Res, 20(4):1042-1052.

[78]ZhangCF, ChenLP, SunL, et al., 2023. BMAL1 collaborates with CLOCK to directly promote DNA double-strand break repair and tumor chemoresistance. Oncogene, 42(13):967-979.

[79]ZhangR, LahensNF, BallanceHI, et al., 2014. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci USA, 111(45):16219-16224.

[80]ZhangZ, ZengPH, GaoWH, et al., 2021. Circadian clock: a regulator of the immunity in cancer. Cell Commun Signal, 19:37.

[81]ZhouL, ZhangZ, NiceE, et al., 2022. Circadian rhythms and cancers: the intrinsic links and therapeutic potentials. J Hematol Oncol, 15:21.

[82]ZhuYF, ZhengY, DaiRY, et al., 2025. Crosstalk between circadian rhythm dysregulation and tumorigenesis, tumor metabolism and tumor immune response. Aging Dis, 16(4):2073-2099.