title: The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway.
abstract: Disruption of the circadian clock has been shown to be associated with tumor development. This study aimed to investigate the role of the core circadian gene Bmal1 in pancreatic cancer (PC). We first found that the levels of Bmal1 were downregulated in PC samples and were closely correlated with the clinicopathological features of patients. To dissect the underlying mechanism, we performed a RNA-seq assay followed by systematic gene function and pathway enrichment analyses. We detected an anti-apoptotic and pro-proliferative transcriptome profile after Bmal1 knockdown in PC cells. Further in vitro and in vivo studies confirmed that Bmal1 overexpression significantly inhibited cell proliferation and invasion and induced G2/M cell cycle arrest, whereas Bmal1 knockdown promoted PC growth, as demonstrated in Bmal1-manipulated AsPC-1 and BxPC-3 cell lines. Our mechanistic studies indicated that Bmal1 could directly bind to the p53 gene promoter and thereby transcriptionally activate the downstream tumor suppressor pathway in a p53-dependent manner. In sum, our findings suggest that Bmal1 acts as an anti-oncogene in PC and represents a potential biomarker for its diagnosis.
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Gastrointestinal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Congying
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xingpeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: Lijuanyang77@163.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: doctorwanrong1970@126.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Wan
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D059467:Transcriptome; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Bmal1; Cell cycle arrest; Circadian clock; P53; Pancreatic cancer