FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation

Ren Liu; Zhihao Zou; Lingwu Chen; Yuanfa Feng; Jianheng Ye; Yulin Deng; Xuejin Zhu; Yixun Zhang; Jundong Lin; Shanghua Cai; Zhenfeng Tang; Yingke Liang; Jianming Lu; Yangjia Zhuo; Zhaodong Han; Xiaohui Ling; Yuxiang Liang; Zongren Wang; Weide Zhong

doi:10.1038/s41419-024-06450-x

Cell Death and Disease (Jan 2024)

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation

Ren Liu,
Zhihao Zou,
Lingwu Chen,
Yuanfa Feng,
Jianheng Ye,
Yulin Deng,
Xuejin Zhu,
Yixun Zhang,
Jundong Lin,
Shanghua Cai,
Zhenfeng Tang,
Yingke Liang,
Jianming Lu,
Yangjia Zhuo,
Zhaodong Han,
Xiaohui Ling,
Yuxiang Liang,
Zongren Wang,
Weide Zhong

Affiliations

Ren Liu: Department of Urology, The First Affiliated Hospital, Sun Yat-sen University
Zhihao Zou: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Lingwu Chen: Department of Urology, The First Affiliated Hospital, Sun Yat-sen University
Yuanfa Feng: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Jianheng Ye: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Yulin Deng: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Xuejin Zhu: Department of Urology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yixun Zhang: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Jundong Lin: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Shanghua Cai: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Zhenfeng Tang: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Yingke Liang: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Jianming Lu: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Yangjia Zhuo: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Zhaodong Han: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Xiaohui Ling: Reproductive Medicine Centre, Huizhou Central People’s Hospital
Yuxiang Liang: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Zongren Wang: Department of Urology, The First Affiliated Hospital, Sun Yat-sen University
Weide Zhong: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology

DOI: https://doi.org/10.1038/s41419-024-06450-x
Journal volume & issue: Vol. 15, no. 1
pp. 1 – 13

Abstract

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Abstract Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

Published in Cell Death and Disease

ISSN: 2041-4889 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General): Cytology
Website: http://www.nature.com/cddis/index.html

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