Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma.
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.
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Qingming
Q
Tang
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Bo
B
Cheng
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Mengru
M
Xie
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Yatao
Y
Chen
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Jiajia
J
Zhao
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Xin
X
Zhou
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China E-mail:chenlili@whuh.com.
Lili
L
Chen
D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D057906:Circadian Clocks / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D000970:Antineoplastic Agents; D017239:Paclitaxel