Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma
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 prote...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002268 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zihao Deng |
| collection | DOAJ |
| description | 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 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 to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α to upregulate FASN transcription via liver X receptor α/sterol regulatory element binding protein 1 axis. Our data reveal 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. |
| format | Article |
| id | doaj-art-005d927d705a4628aa38221c6db14cfe |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-005d927d705a4628aa38221c6db14cfe2025-01-30T05:12:40ZengElsevierJournal of Lipid Research0022-22752025-01-01661100721Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinomaZihao Deng0Lixia Liu1Guantai Xie2Zhenming Zheng3Jieyou Li4Wenchong Tan5Yaotang Deng6Jinxin Zhang7Manfeng Liang8Yingxia Wu9Zhifeng Zhou10Yan Li11Yukui Chen12Yaling Huang13Hairou Su14Guibing Wu15Xiongjie Shi16Shengpei Cen17Yandan Liao18Yilin Liu19Fei Zou20Xuemei Chen21Department of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Hygiene Inspection and Quarantine Science, School of Public Health, Southern Medical University, Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou, ChinaDepartment of Hygiene Inspection and Quarantine Science, School of Public Health, Southern Medical University, Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China; For correspondence: Xuemei ChenExcessive 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 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 to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α to upregulate FASN transcription via liver X receptor α/sterol regulatory element binding protein 1 axis. Our data reveal 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.http://www.sciencedirect.com/science/article/pii/S0022227524002268HCClipid accumulationHsp90αHsp90 inhibitorFASNSREBP1 |
| spellingShingle | 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 Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma Journal of Lipid Research HCC lipid accumulation Hsp90α Hsp90 inhibitor FASN SREBP1 |
| title | Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma |
| title_full | Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma |
| title_fullStr | Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma |
| title_full_unstemmed | Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma |
| title_short | Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma |
| title_sort | hsp90α promotes lipogenesis by stabilizing fasn and promoting fasn transcription via lxrα in hepatocellular carcinoma |
| topic | HCC lipid accumulation Hsp90α Hsp90 inhibitor FASN SREBP1 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002268 |
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