Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma.

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zihao Deng, Lixia Liu, Guantai Xie, Zhenming Zheng, Jieyou Li, Wenchong Tan, Yaotang Deng, Jinxin Zhang, Manfeng Liang, Yingxia Wu, Zhifeng Zhou, Yan Li, Yukui Chen, Yaling Huang, Hairou Su, Guibing Wu, Xiongjie Shi, Shengpei Cen, Yandan Liao, Yilin Liu, Fei Zou, Xuemei Chen
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引用次数: 0

Abstract

Excessive lipid accumulation promotes the occurrence and progression of hepatocellular carcinoma (HCC), accompanied by high levels of fatty acid synthetase (FASN) and more active lipogenesis. Heat shock protein 90 (Hsp90) acts as a chaperone to maintain the stability and activity of the client proteins. Studies have revealed that Hsp90 regulates the lipid metabolism of HCC, but the effect of Hsp90 on FASN still remains unknown. This study aims to discover the mechanism of Hsp90 inhibition on lipid accumulation and investigate the different effects of Hsp90 N-terminal domain inhibitor STA9090 and C-terminal domain inhibitor novobiocin (NB) on FASN protein stability and transcription pathway in HCC. We found that HCC cells tended to store lipids, which could be disrupted by Hsp90 inhibitors in vivo and in vitro. High levels of Hsp90α and FASN in tumor tissue had correlation with poor prognosis of HCC patients and Hsp90α interacted with FASN to maintain its protein stability. Furthermore, N-terminal domain of Hsp90α was essential for process of sterol regulatory element binding protein 1 (SREBP1) to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α (LXRα) to upregulate FASN transcription via LXRα/SREBP1 axis. Our data reveals that Hsp90α promotes lipid accumulation by increasing the protein stability and FASN mRNA transcription, and can be alleviated by Hsp90 inhibitors, which provides a theoretical basis for Hsp90-targeted therapy on lipid metabolism in HCC.

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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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