Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma

Nov 9, 2016Cancer research

The Body Clock Gene Bmal1 Slows Tongue Cancer Growth and Makes It More Sensitive to Paclitaxel

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Abstract

Bmal1 expression levels in tongue squamous cell carcinoma (TSCC) samples are associated with chemotherapy efficacy.

Bmal1 expression is downregulated and exhibits altered rhythmic patterns in TSCC samples and cell lines.
Ectopic Bmal1 inhibits cell proliferation, migration, and invasion in laboratory settings.
In mouse models, Bmal1 overexpression reduces tumor growth.
Bmal1-overexpressing cells show increased apoptosis and greater sensitivity to paclitaxel treatment.
A regulatory connection exists between Bmal1, TERT, and the transcriptional repressor EZH2, which enhances chemotherapy-induced apoptosis.
Clinical findings suggest a positive correlation between paclitaxel efficacy and Bmal1 expression levels in TSCC.

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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.

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Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma

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