The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Issue 2 (28th February 2016)

• Record Type: Journal Article
• Authors: Jiang, Weiliang; Zhao, Senlin; Jiang, Xiaohua; Zhang, Erquan; Hu, Guoyong; Hu, Bin; Zheng, Ping; Xiao, Junhua; Lu, Zhanjun; Lu, Yingying; Ni, Jianbo; Chen, Congying; Wang, Xingpeng; Yang, Lijuan; Wan, Rong
• Is Part Of: Cancer letters. Volume 371:Issue 2(2016)
• Page Start: 314
• Page End: 325
• Publication Date: 2016-02-28
• Subjects: Circadian clock -- Bmal1 -- Pancreatic cancer -- P53 -- Cell cycle arrest -- Apoptosis; PC pancreatic cancer -- ChIP chromatin immunoprecipitation -- GO gene ontology -- KEGG Kyoto Encyclopedia of Genes and Genomes -- CCG clock-controlled gene; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.12.002
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: The expression level of Bmal1 is downregulated in pancreatic cancer (PC) tissues. Bmal 1 significantly inhibits the proliferation and invasion of PC cells, both in vitro and in vivo . Bmal1 could directly bind to the p53 gene promoter. Bmal1 is able to induce apoptosis and G2/M cell cycle arrest in PC cells in a p53-dependent manner. 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.