Abstract
Circadian clock genes regulate cancer development and chemotherapy susceptibility. Accordingly, chronotherapy based on circadian phenotypes might be applied to improve therapeutic efficacy. In this study, we investigated whether the circadian clock gene Bmal1 inhibited tumor development and increased paclitaxel sensitivity in tongue squamous cell carcinoma (TSCC). Bmal1 expression was downregulated and its rhythmic pattern of expression was affected in TSCC samples and cell lines. Ectopic Bmal1 inhibited cell proliferation, migration and invasion in vitro, and tumor growth in mouse xenograft models of TSCC. After exposure to paclitaxel, Bmal1-overexpressing cells displayed a relative increase in apoptosis and were more susceptible to paclitaxel treatment in vivo Mechanistic investigations suggested a regulatory connection between Bmal1, TERT, and the oncogenic transcriptional repressor EZH2 (enhancer of zeste homolog 2), the recruitment of which to the TERT promoter increased paclitaxel-induced apoptosis and cell growth inhibition. Clinically, paclitaxel efficacy correlated positively with Bmal1 expression levels in TSCC. Overall, our results identified Bmal1 as a novel tumor suppressor gene that elevates the sensitivity of cancer cells to paclitaxel, with potential implications as a chronotherapy timing biomarker in TSCC. Cancer Res; 77(2); 532-44. ©2016 AACR.
Highlights
Most physiological, biochemical, and behavioral processes in mammals follow circadian rhythm, which is generated by an endogenous clock system with an approximately 24-hour cycle [1, 2]
To provide new insights into the mechanism by which the circadian system influences tumorigenic process and treatment, we performed the study and showed that Bmal1 expression level and rhythmic pattern were affected in both tongue squamous cell carcinoma (TSCC) samples and cell lines
Similar to the results in ovarian cancer [12], colorectal cancer [13], and pancreatic tumors [30], Bmal1 overexpression significantly inhibited proliferation, migration, and invasion of TSCC cells, suggesting that Bmal1 might act as an anti-TSCC gene
Summary
Biochemical, and behavioral processes in mammals follow circadian rhythm, which is generated by an endogenous clock system with an approximately 24-hour cycle [1, 2]. In addition to the functional roles in biologic rhythm, increasing evidences indicate that Bmal participates in the hallmarks of cancer, including proliferative signaling maintenance, cell death resistance, replicative immortality, invasion and metastasis activation, and energy metabolism reconfiguration [5,6,7,8,9]. Chronic circadian misalignment, such as fragmented sleep, significantly accelerates the incidence of various tumors [10, 11]. It has been reported that Bmal has antitumor roles in ovarian cancer
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