Hsp90 Inhibitor STA9090 Sensitizes Hepatocellular Carcinoma to Hyperthermia-Induced DNA Damage by Suppressing DNA-PKcs Protein Stability and mRNA Transcription

• Published in: Molecular cancer therapeutics Vol. 20; no. 10; pp. 1880 - 1892
• Main Authors: Liu, Lixia, Deng, Yaotang, Zheng, Zhenming, Deng, Zihao, Zhang, Jinxin, Li, Jieyou, Liang, Manfeng, Zhou, Xueqiong, Tan, Wenchong, Yang, Hongjun, Neckers, Leonard M, Zou, Fei, Chen, Xuemei
• Format: Journal Article
• Language: English
• Published: United States 01.10.2021
• Subjects: Animals; Apoptosis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Proliferation; DNA Damage; DNA Repair; DNA-Activated Protein Kinase - chemistry; Gene Expression Regulation, Neoplastic - drug effects; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Hyperthermia, Induced - adverse effects; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prognosis; Protein Stability; RNA, Messenger - genetics; Survival Rate; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0215

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 (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 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 mRNA level, which provide a theoretical basis for the promising combination therapy of hyperthermia and Hsp90 inhibitor in HCC.