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 experimenta...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.展开更多
基金supported by the Ministry of Science and Technology of the People’s Republic of China(Nos.2020YFA0803300 and 2021YFA0805600)the National Natural Science Foundation of China(Nos.92157113,82072630,82173114,82072903,82272872,82002811,82188102,and 82030074)+2 种基金the Zhejiang Natural Science Foundation Key Project(Nos.LD22H160002 and LD21H160003)the Zhejiang Natural Science Foundation Discovery Project(No.LQ22H160023)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(No.2019R01001),China.
文摘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.
