Depletion of Kruppel-like factor 15 sensitized gliomas to temozolomide cytotoxicity through O6-methylguanine-DNA methyl-transferase

Biochemistry and Biophysics Reports

Xiaohua Wang¹  Yumei Zhang²  Xinjuan Qu³  Xuelai Liu³  Zhan Shi⁴ 

[1] Corresponding author.;Department of Neurology, Linyi Hospital of Traditional Chinese Medicine, Shandong, 276002, China;Department of Neurosurgery, Linyi Hospital of Traditional Chinese Medicine, Shandong, 276002, China;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, 210002, China;

关键词: Giomas;    Chemoresistance;    DNA damage Repair;    Krupple-like factor 15;    Transcription activator;    O6-methylguanine-DNA methyl-Transferase;   

DOI  :  

来源: DOAJ

【 摘 要 】

Temozolomide (TMZ)-based chemotherapy is a standard strategy for gliomas, although chemoresistance remains a major therapeutic challenge. The chemical mechanism by which TMZ induces cell death is DNA methylation, leading to double-stranded breaks (DSBs) and thus to apoptosis. However, TMZ-induced N6-meG sites are efficiently repaired and mediated by the DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT), leading to TMZ resistance. KLF15, a member of the Kruppel-like factors family, mainly functions as transcription factor and potential suppressor gene by inhibiting proliferation, migration, and inducing apoptosis. However, the roles and regulatory mechanisms of KLF15 in glioma tumorigenesis and chemoresistance are poorly understood. In this study, KLF15 expression was upregulated in glioma tissues and cell lines upon TMZ treatment. Knockdown of KLF15 amplified TMZ-induced repression of cell proliferation, while KLF15 overexpression reversed this process. Mechanistically, KLF15 functioned as a transcriptional activator of MGMT. Moreover, KLF15 knockdown sensitized tumors to TMZ treatment in vivo. Taken together, these results suggested that KLF15 up-regulated MGMT through direct binding to the promoter of MGMT, which plays an important role in glioma resistance to TMZ, and which may be a potential target for cancer diagnosis and treatment.

【 授权许可】

Unknown