Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity.
The Bmal1 gene plays a key role in controlling circadian rhythms. To better understand how the Bmal1 gene affects tumour growth and the response to anti-cancer drugs, we examined the effect of knockdown of Bmal1 by RNAi both in vitro and in vivo. Down-regulation of Bmal1 gene expression accelerated cell proliferation in vitro and promoted tumour growth in mice. Suppressing Bmal1 expression in murine colon cancer cells (C26) and fibroblast cells (L929) decreased apoptosis induced by Etoposid, reduced the distribution of cells in the G2/M phases treated by Docetaxel and decreased DNA damage induced by Cisplatin. Loss of Bmal1 reduced the expression of per1, per2, per3, wee1 and p53. The expression of p21 and c-myc was also altered in certain cell lines. However, Bmal1 deficiency increased the protein levels of cdc2, cyclin B1, cyclin D1 and cyclin E. Wee1 and cyclin A expression was minimally altered. Thus, the circadian clock gene Bmal1 plays a role in regulating tumour cell apoptosis, cell-cycle progression and DNA damage response and in homoeostasis regulation. Down-regulation of Bmal1 accelerates the development of tumours and may influence the response to anti-cancer drugs.
Zeng
Zhao-Lei
ZL
State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, P.R. China.
Wu
Ming-Wei
MW
Sun
Jian
J
Sun
Yue-Li
YL
Cai
Yu-Chen
YC
Huang
Yi-Jun
YJ
Xian
Li-Jian
LJ
D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001683:Biological Clocks / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004260:DNA Repair; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D006706:Homeostasis; D051379:Mice; D034741:RNA, Small Interfering / Q000494:pharmacology
D056930:ARNTL Transcription Factors; D000970:Antineoplastic Agents; C538961:Bmal1 protein, mouse; D034741:RNA, Small Interfering