昼夜节律基因<italic style="font-style: italic">CLOCK</italic>与<italic style="font-style: italic">BMAL1</italic>在癌症中的作用：机制解析与治疗策略

沈玉丽; 赵玉倩; 孙雪; 姬贵梅; 许大千; 王征

doi:10.1631/jzus.B2500455

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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

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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
Circadian genes CLOCK and BMAL1 in cancer: mechanistic insights and therapeutic strategies
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第10期页码：935-948
Affiliations：

1.Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
2.Cancer Center, Zhejiang University, Hangzhou 310029, China
3.Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China
4.Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310029, China
Funds：

the Ministry of Science and Technology of the People’s Republic of China(2020YFA0803300;2021YFA0805600);the National Natural Science Foundation of China(92157113;82072630;82173114;82072903;82272872;82002811;82188102;82030074);the Zhejiang Natural Science Foundation Key Project(LD22H160002;LD21H160003);the Zhejiang Natural Science Foundation Discovery Project(LQ22H160023);the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(2019R01001)
DOI：10.1631/jzus.B2500455
中图分类号：
CSTR：
收稿：2025-07-30，

修回：2025-09-14，

纸质出版：2025-10-20
Accepted：

沈玉丽,赵玉倩,孙雪等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(10):935-948.

Yuli SHEN, Yuqian ZHAO, Xue SUN, et al. Circadian genes CLOCK and BMAL1 in cancer: mechanistic insights and therapeutic strategies[J]. Journal of zhejiang university-science b, 2025, 26(10): 935-948.
沈玉丽,赵玉倩,孙雪等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(10):935-948. DOI： 10.1631/jzus.B2500455.

Yuli SHEN, Yuqian ZHAO, Xue SUN, et al. Circadian genes CLOCK and BMAL1 in cancer: mechanistic insights and therapeutic strategies[J]. Journal of zhejiang university-science b, 2025, 26(10): 935-948. DOI： 10.1631/jzus.B2500455.

摘要

昼夜节律时钟作为生物体中高度保守的时间维持系统，可通过精确调控基因表达的周期性波动维持机体生理稳态。大量临床与实验证据表明，昼夜节律紊乱与多种恶性肿瘤的发生发展密切相关。研究显示，肿瘤组织中存在昼夜节律基因表达谱的特征性改变，主要表现为核心时钟元件（特别是CLOCK与BMAL1）的功能失调及其下游靶基

因的广泛调控异常。值得注意的是，

CLOCK

基因展现出非经典致癌功能，包括通过组蛋白乙酰转移酶活性进行表观遗传调控，以及对癌症通路实施不依赖于昼夜节律的调控作用。本文系统阐述了CLOCK/BMAL1介导的致癌机制，涵盖细胞周期调控、DNA损伤应答、代谢重编程及肿瘤微环境重塑等多维度效应。在治疗策略方面，本文重点关注时序营养干预、节律药理学调控及治疗方案优化等前沿方向，并对未来发展前景进行展望。本文聚焦的研究突破不仅加深了我们对昼夜节律调控在癌症生物学中重要作用的理解，更为时序治疗肿瘤学的发展提供了新视角，尤其是通过靶向昼夜节律蛋白的非经典功能来开发创新的抗癌策略。

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.

关键词

Keywords

references

Alhopuro P , Björklund M , Sammalkorpi H , et al. , 2010 . Mutations in the circadian gene CLOCK in colorectal cancer . Mol Cancer Res , 8 ( 7 ): 952 - 960 . https://doi.org/10.1158/1541-7786.MCR-10-0086 https://doi.org/10.1158/1541-7786.MCR-10-0086

Amiama-Roig A , Verdugo-Sivianes EM , Carnero A , et al. , 2022 . Chronotherapy: circadian rhythms and their influence in cancer therapy . Cancers , 14 ( 20 ): 5071 . https://doi.org/10.3390/cancers14205071 https://doi.org/10.3390/cancers14205071

Boivin DB , Boudreau P , 2014 . Impacts of shift work on sleep and circadian rhythms . Pathol Biol , 62 ( 5 ): 292 - 301 . https://doi.org/10.1016/j.patbio.2014.08.001 https://doi.org/10.1016/j.patbio.2014.08.001

Burgermeister E , Battaglin F , Eladly F , 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 . https://doi.org/10.1016/j.ebiom.2019.07.004 https://doi.org/10.1016/j.ebiom.2019.07.004

Chan P , Nagai Y , Wu QL , 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 . https://doi.org/10.1093/neuonc/noaf089 https://doi.org/10.1093/neuonc/noaf089

Chen PW , Hsu WH , Chang A , et al. , 2020 . Circadian regulator CLOCK recruits immune-suppressive microglia into the GBM tumor microenvironment . Cancer Discov , 10 ( 3 ): 371 - 381 . https://doi.org/10.1158/2159-8290.CD-19-0400 https://doi.org/10.1158/2159-8290.CD-19-0400

Cho H , Zhao X , Hatori M , et al. , 2012 . Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β . Nature , 485 ( 7396 ): 123 - 127 . https://doi.org/10.1038/nature11048 https://doi.org/10.1038/nature11048

Cotta-Ramusino C , McDonald ER III , Hurov K , 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 . https://doi.org/10.1126/science.1203430 https://doi.org/10.1126/science.1203430

Curtis AM , Bellet MM , Sassone-Corsi P , et al. , 2014 . Circadian clock proteins and immunity . Immunity , 40 ( 2 ): 178 - 186 . https://doi.org/10.1016/j.immuni.2014.02.002 https://doi.org/10.1016/j.immuni.2014.02.002

Damato AR , Luo JQ , Katumba RGN , et al. , 2021 . Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study . Neuro-Oncol Adv , 3 ( 1 ): vdab041 . https://doi.org/10.1093/noajnl/vdab041 https://doi.org/10.1093/noajnl/vdab041

Dong Z , Zhang GX , Qu M , et al. , 2019 . Targeting glioblastoma stem cells through disruption of the circadian clock . Cancer Discov , 9 ( 11 ): 1556 - 1573 . https://doi.org/10.1158/2159-8290.CD-19-0215 https://doi.org/10.1158/2159-8290.CD-19-0215

Doruk YU , Yarparvar D , Akyel YK , 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 . https://doi.org/10.1074/jbc.RA119.011332 https://doi.org/10.1074/jbc.RA119.011332

Duong HA , Robles MS , Knutti D , et al. , 2011 . A molecular mechanism for circadian clock negative feedback . Science , 332 ( 6036 ): 1436 - 1439 . https://doi.org/10.1126/science.1196766 https://doi.org/10.1126/science.1196766

Elhanani O , Ben-Uri R , Keren L , 2023 . Spatial profiling technologies illuminate the tumor microenvironment . Cancer Cell , 41 ( 3 ): 404 - 420 . https://doi.org/10.1016/j.ccell.2023.01.010 https://doi.org/10.1016/j.ccell.2023.01.010

Fagiani F , di Marino D , Romagnoli A , et al. , 2022 . Molecular regulations of circadian rhythm and implications for physiology and diseases . Signal Transduct Target Ther , 7 : 41 . https://doi.org/10.1038/s41392-022-00899-y https://doi.org/10.1038/s41392-022-00899-y

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 . https://doi.org/10.1016/j.tjnut.2023.11.033 https://doi.org/10.1016/j.tjnut.2023.11.033

Farshadi E , Yan J , Leclere P , 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 . https://doi.org/10.1080/15384101.2018.1558638 https://doi.org/10.1080/15384101.2018.1558638

Fortin BM , Pfeiffer SM , Insua-Rodríguez J , et al. , 2024 . Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade . Nat Immunol , 25 ( 7 ): 1257 - 1269 . https://doi.org/10.1038/s41590-024-01859-0 https://doi.org/10.1038/s41590-024-01859-0

Fortin BM , Mahieu AL , Fellows RC , et al. , 2025 . The diverse roles of the circadian clock in cancer . Nat Cancer , 6 ( 5 ): 753 - 767 . https://doi.org/10.1038/s43018-025-00981-8 https://doi.org/10.1038/s43018-025-00981-8

Fuhr L , El-Athman R , Scrima R , 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 . https://doi.org/10.1016/j.ebiom.2018.07.002 https://doi.org/10.1016/j.ebiom.2018.07.002

Gaucher J , Montellier E , Sassone-Corsi P , 2018 . Molecular cogs: interplay between circadian clock and cell cycle . Trends Cell Biol , 28 ( 5 ): 368 - 379 . https://doi.org/10.1016/j.tcb.2018.01.006 https://doi.org/10.1016/j.tcb.2018.01.006

Gotoh T , Vila-Caballer M , Santos CS , et al. , 2014 . The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells . Mol Biol Cell , 25 ( 19 ): 3081 - 3093 . https://doi.org/10.1091/mbc.E14-05-0993 https://doi.org/10.1091/mbc.E14-05-0993

Grabe S , Ananthasubramaniam B , Herzel H , 2024 . Quantification of circadian rhythms in mammalian lung tissue snapshot data . Sci Rep , 14 : 16238 . https://doi.org/10.1038/s41598-024-66694-7 https://doi.org/10.1038/s41598-024-66694-7

Han ZY , Zhang C , An JX , et al. , 2025 . Directly evolved nanovaccines modulate disrupted circadian rhythm and enhance cancer immunotherapy . Adv Mater , 37 ( 34 ): 2502602 . https://doi.org/10.1002/adma.202502602 https://doi.org/10.1002/adma.202502602

Hanahan D , 2022 . Hallmarks of cancer: new dimensions . Cancer Discov , 12 ( 1 ): 31 - 46 . https://doi.org/10.1158/2159-8290.CD-21-1059 https://doi.org/10.1158/2159-8290.CD-21-1059

He BK , Nohara K , Park N , 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 . https://doi.org/10.1016/j.cmet.2016.03.007 https://doi.org/10.1016/j.cmet.2016.03.007

Huang LH , Huang CY , Liu YW , 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 . https://doi.org/10.3390/ijms25115748 https://doi.org/10.3390/ijms25115748

Huang N , Chelliah Y , Shan YL , et al. , 2012 . Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex . Science , 337 ( 6091 ): 189 - 194 . https://doi.org/10.1126/science.1222804 https://doi.org/10.1126/science.1222804

Jiang WL , Zhao SL , Jiang XH , 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 . https://doi.org/10.1016/j.canlet.2015.12.002 https://doi.org/10.1016/j.canlet.2015.12.002

Kamal IR , El-Atty SMA , El-Zoghdy SF , et al. , 2025 . Intelligent deep learning model for targeted cancer drug delivery . Sci Rep , 15 : 19068 . https://doi.org/10.1038/s41598-025-96149-6 https://doi.org/10.1038/s41598-025-96149-6

Kiessling S , Beaulieu-Laroche L , Blum ID , et al. , 2017 . Enhancing circadian clock function in cancer cells inhibits tumor growth . BMC Biol , 15 : 13 . https://doi.org/10.1186/s12915-017-0349-7 https://doi.org/10.1186/s12915-017-0349-7

Kim DW , Mayer C , Lee MP , 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 . https://doi.org/10.1098/rsif.2023.0030 https://doi.org/10.1098/rsif.2023.0030

Leung C , Gérard C , Gonze D , 2023 . Modeling the circadian control of the cell cycle and its consequences for cancer chronotherapy . Biology , 12 ( 4 ): 612 . https://doi.org/10.3390/biology12040612 https://doi.org/10.3390/biology12040612

Lévi FA , Okyar A , Hadadi E , et al. , 2024 . Circadian regulation of drug responses: toward sex-specific and personalized chronotherapy . Annu Rev Pharmacol Toxicol , 64 : 89 - 114 . https://doi.org/10.1146/annurev-pharmtox-051920-095416 https://doi.org/10.1146/annurev-pharmtox-051920-095416

Li MD , 2022 . Clock-modulated checkpoints in time-restricted eating . Trends Mol Med , 28 ( 1 ): 25 - 35 . https://doi.org/10.1016/j.molmed.2021.10.006 https://doi.org/10.1016/j.molmed.2021.10.006

Liu JL , Xu X , Rixiati Y , 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 . https://doi.org/10.1016/j.cmet.2024.04.019 https://doi.org/10.1016/j.cmet.2024.04.019

Liu T , Wang Z , Ye LG , 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 . https://doi.org/10.1038/s41556-022-01061-0 https://doi.org/10.1038/s41556-022-01061-0

Longo VD , Panda S , 2016 . Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan . Cell Metab , 23 ( 6 ): 1048 - 1059 . https://doi.org/10.1016/j.cmet.2016.06.001 https://doi.org/10.1016/j.cmet.2016.06.001

Ma YR , Ren X , Patel N , et al. , 2020 . Nobiletin , a citrus polymethox yflavone, enhances the effects of bicalutamide on prostate cancer cells via down regulation of NF-κB, STAT 3 , and ERK activation . RSC Adv, 10 ( 17 ): 10254 - 10262 . https://doi.org/10.1039/c9ra10020b https://doi.org/10.1039/c9ra10020b

Miki T , Matsumoto T , Zhao ZY , et al. , 2013 . p53 regulates Period2 expression and the circadian clock . Nat Commun , 4 : 2444 . https://doi.org/10.1038/ncomms3444 https://doi.org/10.1038/ncomms3444

Mure LS , Le HD , Benegiamo G , et al. , 2018 . Diurnal transcriptome atlas of a primate across major neural and peripheral tissues . Science , 359 ( 6381 ): eaao0318 . https://doi.org/10.1126/science.aao0318 https://doi.org/10.1126/science.aao0318

Negrini S , Gorgoulis VG , Halazonetis TD , 2010 . Genomic instability — an evolving hallmark of cancer . Nat Rev Mol Cell Biol , 11 ( 3 ): 220 - 228 . https://doi.org/10.1038/nrm2858 https://doi.org/10.1038/nrm2858

Nguyen KD , Fentress SJ , Qiu YF , et al. , 2013 . Circadian gene Bmal1 regulates diurnal oscillations of Ly6C hi inflammatory monocytes . Science , 341 ( 6153 ): 1483 - 1488 . https://doi.org/10.1126/science.1240636 https://doi.org/10.1126/science.1240636

Ortega-Campos SM , Verdugo-Sivianes EM , Amiama-Roig A , et al. , 2023 . Interactions of circadian clock genes with the hallmarks of cancer . Biochim Biophys Acta Rev Cancer , 1878 ( 3 ): 188900 . https://doi.org/10.1016/j.bbcan.2023.188900 https://doi.org/10.1016/j.bbcan.2023.188900

Pang LZ , Dunterman M , Xuan WJ , et al. , 2023 . Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma . Cell Rep , 42 ( 2 ): 112127 . https://doi.org/10.1016/j.celrep.2023.112127 https://doi.org/10.1016/j.celrep.2023.112127

Papagiannakopoulos T , Bauer MR , Davidson SM , et al. , 2016 . Circadian rhythm disruption promotes lung tumorigenesis . Cell Metab , 24 ( 2 ): 324 - 331 . https://doi.org/10.1016/j.cmet.2016.07.001 https://doi.org/10.1016/j.cmet.2016.07.001

Patke A , Young MW , Axelrod S , 2020 . Molecular mechanisms and physiological importance of circadian rhythms . Nat Rev Mol Cell Biol , 21 ( 2 ): 67 - 84 . https://doi.org/10.1038/s41580-019-0179-2 https://doi.org/10.1038/s41580-019-0179-2

Pavlova NN , Thompson CB , 2016 . The emerging hallmarks of cancer metabolism . Cell Metab , 23 ( 1 ): 27 - 47 . https://doi.org/10.1016/j.cmet.2015.12.006 https://doi.org/10.1016/j.cmet.2015.12.006

Peng F , Lu JX , Su KY , et al. , 2024 . Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis . Cell Metab , 36 ( 7 ): 1598 - 1618.e11 . https://doi.org/10.1016/j.cmet.2024.04.018 https://doi.org/10.1016/j.cmet.2024.04.018

Pu H , Bailey LC , Bauer LG , et al. , 2025 . Pharmacological targeting of BMAL1 modulates circadian and immune pathways . Nat Chem Biol , 21 ( 5 ): 736 - 745 . https://doi.org/10.1038/s41589-025-01863-x https://doi.org/10.1038/s41589-025-01863-x

Qi GY , Guo R , Tian HY , 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 . https://doi.org/10.1016/j.bbalip.2018.02.009 https://doi.org/10.1016/j.bbalip.2018.02.009

Qu M , Zhang GX , Qu H , 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 . https://doi.org/10.1073/pnas.2214829120 https://doi.org/10.1073/pnas.2214829120

Quail DF , Joyce JA , 2013 . Microenvironmental regulation of tumor progression and metastasis . Nat Med , 19 ( 11 ): 1423 - 1437 . https://doi.org/10.1038/nm.3394 https://doi.org/10.1038/nm.3394

Queiroz JDN , Macedo RCO , Tinsley GM , et al. , 2021 . Time-restricted eating and circadian rhythms: the biological clock is ticking . Crit Rev Food Sci Nutr , 61 ( 17 ): 2863 - 2875 . https://doi.org/10.1080/10408398.2020.1789550 https://doi.org/10.1080/10408398.2020.1789550

Ripperger JA , Schibler U , 2006 . Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions . Nat Genet , 38 ( 3 ): 369 - 374 . https://doi.org/10.1038/ng1738 https://doi.org/10.1038/ng1738

Sancar A , van Gelder RN , 2021 . Clocks, cancer, and chronochemotherapy . Science , 371 ( 6524 ): eabb0738 . https://doi.org/10.1126/science.abb0738 https://doi.org/10.1126/science.abb0738

Sancar A , Lindsey-Boltz LA , Kang TH , et al. , 2010 . Circadian clock control of the cellular response to DNA damage . FEBS Lett , 584 ( 12 ): 2618 - 2625 . https://doi.org/10.1016/j.febslet.2010.03.017 https://doi.org/10.1016/j.febslet.2010.03.017

Schrader LA , Ronnekleiv-Kelly SM , Hogenesch JB , et al. , 2024 . Circadian disruption, clock genes, and metabolic health . J Clin Invest , 134 ( 14 ): e170998 . https://doi.org/10.1172/JCI170998 https://doi.org/10.1172/JCI170998

Shi D , Fang GF , Chen QY , et al. , 2023 . Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism . BMC Med , 21 : 417 . https://doi.org/10.1186/s12916-023-03131-y https://doi.org/10.1186/s12916-023-03131-y

Slat EA , Sponagel J , Marpegan L , et al. , 2017 . Cell-intrinsic, Bmal1-dependent circadian regulation of temozolomide sensitivity in glioblastoma . J Biol Rhythms , 32 ( 2 ): 121 - 129 . https://doi.org/10.1177/0748730417696788 https://doi.org/10.1177/0748730417696788

Sulli G , Manoogian ENC , Taub PR , 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 . https://doi.org/10.1016/j.tips.2018.07.003 https://doi.org/10.1016/j.tips.2018.07.003

Terzibasi-Tozzini E , Martinez-Nicolas A , Lucas-Sánchez A , 2017 . The clock is ticking. Ageing of the circadian system: from physiology to cell cycle . Semin Cell Dev Biol , 70 : 164 - 176 . https://doi.org/10.1016/j.semcdb.2017.06.011 https://doi.org/10.1016/j.semcdb.2017.06.011

Wang C , Zeng Q , Gül ZM , et al. , 2024 . Circadian tumor infiltration and function of CD8 + T cells dictate immunotherapy efficacy . Cell , 187 ( 11 ): 2690 - 2702.e17 . https://doi.org/10.1016/j.cell.2024.04.015 https://doi.org/10.1016/j.cell.2024.04.015

Wang YP , Qian RZ , Sun N , 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 . https://doi.org/10.3892/mmr.2015.3247 https://doi.org/10.3892/mmr.2015.3247

Wang YP , Sun N , Lu C , et al. , 2017 . Upregulation of circadian gene ‘hClock’ contribution to metastasis of colorectal cancer . Int J Oncol , 50 ( 6 ): 2191 - 2199 . https://doi.org/10.3892/ijo.2017.3987 https://doi.org/10.3892/ijo.2017.3987

Wang Z , Ma LN , Meng Y , et al. , 2024 . The interplay of the circadian clock and metabolic tumorigenesis . Trends Cell Biol , 34 ( 9 ): 742 - 755 . https://doi.org/10.1016/j.tcb.2023.11.004 https://doi.org/10.1016/j.tcb.2023.11.004

Wei T , Cheng Y , Ge JR , 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 . https://doi.org/10.1111/cas.70098 https://doi.org/10.1111/cas.70098

Wu DL , Rastinejad F , 2017 . Structural characterization of mammalian bHLH-PAS transcription factors . Curr Opin Struct Biol , 43 : 1 - 9 . https://doi.org/10.1016/j.sbi.2016.09.011 https://doi.org/10.1016/j.sbi.2016.09.011

Wu DL , Su XY , Potluri N , et al. , 2016 . NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors . eLife , 5 : e18790 . https://doi.org/10.7554/eLife.18790 https://doi.org/10.7554/eLife.18790

Wu YC , Tao BR , Zhang TY , et al. , 2019 . Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion . Front Immunol , 10 : 2451 . https://doi.org/10.3389/fimmu.2019.02451 https://doi.org/10.3389/fimmu.2019.02451

Xu DQ , Shao F , Bian XL , et al. , 2021 . The evolving landscape of noncanonical functions of metabolic enzymes in cancer and other pathologies . Cell Metab , 33 ( 1 ): 33 - 50 . https://doi.org/10.1016/j.cmet.2020.12.015 https://doi.org/10.1016/j.cmet.2020.12.015

Xuan WJ , Khan F , James CD , et al. , 2021 . Circadian regulation of cancer cell and tumor microenvironment crosstalk . Trends Cell Biol , 31 ( 11 ): 940 - 950 . https://doi.org/10.1016/j.tcb.2021.06.008 https://doi.org/10.1016/j.tcb.2021.06.008

Xuan WJ , Hsu WH , Khan F , et al. , 2022 . Circadian regulator CLOCK drives immunosuppression in glioblastoma . Cancer Immunol Res , 10 ( 6 ): 770 - 784 . https://doi.org/10.1158/2326-6066.CIR-21-0559 https://doi.org/10.1158/2326-6066.CIR-21-0559

Yip HYK , Papa A , 2021 . Signaling pathways in cancer: therapeutic targets, combinatorial treatments, and new developments . Cells , 10 ( 3 ): 659 . https://doi.org/10.3390/cells10030659 https://doi.org/10.3390/cells10030659

Yoo SH , Mohawk JA , Siepka SM , et al. , 2013 . Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm . Cell , 152 ( 5 ): 1091 - 1105 . https://doi.org/10.1016/j.cell.2013.01.055 https://doi.org/10.1016/j.cell.2013.01.055

Zeng YE , Guo ZC , Wu MQ , et al. , 2024 . Circadian rhythm regulates the function of immune cells and participates in the development of tumors . Cell Death Discov , 10 : 199 . https://doi.org/10.1038/s41420-024-01960-1 https://doi.org/10.1038/s41420-024-01960-1

Zeng ZL , Luo HY , Yang J , et al. , 2014 . Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer . Clin Cancer Res , 20 ( 4 ): 1042 - 1052 . https://doi.org/10.1158/1078-0432.CCR-13-0171 https://doi.org/10.1158/1078-0432.CCR-13-0171

Zhang CF , Chen LP , Sun L , et al. , 2023 . BMAL1 collaborates with CLOCK to directly promote DNA double-strand break repair and tumor chemoresistance . Oncogene , 42 ( 13 ): 967 - 979 . https://doi.org/10.1038/s41388-023-02603-y https://doi.org/10.1038/s41388-023-02603-y

Zhang R , Lahens NF , Ballance HI , et al. , 2014 . A circadian gene expression atlas in mammals: implications for biology and medicine . Proc Natl Acad Sci USA , 111 ( 45 ): 16219 - 16224 . https://doi.org/10.1073/pnas.1408886111 https://doi.org/10.1073/pnas.1408886111

Zhang Z , Zeng PH , Gao WH , et al. , 2021 . Circadian clock: a regulator of the immunity in cancer . Cell Commun Signal , 19 : 37 . https://doi.org/10.1186/s12964-021-00721-2 https://doi.org/10.1186/s12964-021-00721-2

Zhou L , Zhang Z , Nice E , et al. , 2022 . Circadian rhythms and cancers: the intrinsic links and therapeutic potentials . J Hematol Oncol , 15 : 21 . https://doi.org/10.1186/s13045-022-01238-y https://doi.org/10.1186/s13045-022-01238-y

Zhu YF , Zheng Y , Dai RY , et al. , 2025 . Crosstalk between circadian rhythm dysregulation and tumorigenesis, tumor metabolism and tumor immune response . Aging Dis , 16 ( 4 ): 2073 - 2099 . https://doi.org/10.14336/AD.2024.0533 https://doi.org/10.14336/AD.2024.0533

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Co-regulation of circadian clock genes and microRNAs in bone metabolism

Electromagnetic field exposure as a plausible approach to enhance the proliferation and differentiation of mesenchymal stem cells in clinically relevant scenarios

Lymphatic vasculature in tumor metastasis and immunobiology

Ethical considerations of cellular immunotherapy for cancer

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

Circadian genes CLOCK and BMAL1 in cancer: mechanistic insights and therapeutic strategies

DOI：10.1631/jzus.B2500455

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