癌症研究
热休克蛋白90
抄写(语言学)
热休克蛋白
DNA损伤
分子生物学
生物
DNA
细胞生物学
基因
生物化学
语言学
哲学
作者
Lixia Liu,Yaotang Deng,Zhaoqiang Zheng,Zihao Deng,Jinxin Zhang,Jieyou Li,Manfeng Liang,Xueqiong Zhou,Wenchong Tan,Hongjun Yang,Leonard Μ. Neckers,Fei Zou,Xuemei Chen
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2021-08-10
卷期号:20 (10): 1880-1892
被引量:7
标识
DOI:10.1158/1535-7163.mct-21-0215
摘要
As a conserved molecular chaperone, heat shock protein 90 (Hsp90) maintains the stability and homeostasis of oncoproteins and helps cancer cells survive. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a pivotal role in the non-homologous end joining pathway for DNA double-strand breaks (DSB) repair. Tumor cells contain higher levels of DNA-PKcs to survive by the hostile tumor microenvironment and various antitumor therapies. Here, we showed that increased levels of Hsp90α, Hsp90β, and DNA-PKcs correlated with a poor overall survival in hepatocellular carcinoma (HCC). We revealed that Hsp90 N-terminal domain and C-terminal domain have different effects on DNA-PKcs protein and mRNA levels. The stability of DNA-PKcs depended on Hsp90α N-terminal nucleotide binding domain. Transcription factor SP1 regulates the transcription of PRKDC (gene name of DNA-PKcs) and is a client protein of Hsp90. Inhibition of Hsp90 N-terminal by STA9090 decreased the location of Hsp90α in nucleus, Hsp90α-SP1 interaction, SP1 level, and the binding of Hsp90α/SP1 at the proximal promoter region of PRKDC Because hyperthermia induces DSBs with increases level of DNA-PKcs, combined STA9090 treatment with hyperthermia effectively delayed the tumor growth and significantly decreased DNA-PKcs levels in xenografts model. Consistently, inhibition of Hsp90 increased the number of heat shock-induced γ-H2AX foci and delayed the repair of DSBs. Altogether, our results suggest that Hsp90 inhibitor STA9090 decreases DNA-PKcs protein stability and PRKDC mRNA level, which provide a theoretical basis for the promising combination therapy of hyperthermia and Hsp90 inhibitor in HCC.
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