Research Papers:

Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma

Haiping Tang _, Yuling Chen, Xiaohui Liu, Shiyu Wang, Yang Lv, Di Wu, Qingtao Wang, Minkui Luo and Haiteng Deng

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Oncotarget. 2016; 7:38822-38834. https://doi.org/10.18632/oncotarget.9615

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Haiping Tang1, Yuling Chen1, Xiaohui Liu1, Shiyu Wang2, Yang Lv2, Di Wu2, Qingtao Wang3, Minkui Luo4, Haiteng Deng1

1MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China

2Center of Nephrology, The General Hospital of the PLA, Beijing, China

3Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

4Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence to:

Haiteng Deng, email: [email protected]

Keywords: renal cancer, HSP60, proteostasis, reactive oxygen species, tumorigenesis

Received: January 07, 2016    Accepted: May 05, 2016    Published: May 26, 2016


In the present study, we demonstrate that HSP60 is unequivocally downregulated in clear cell renal cell carcinoma (ccRCC) tissues compared to pericarcinous tissues. Overexpression of HSP60 in ccRCC cancer cells suppresses cell growth. HSP60 knockdown increases cell growth and proliferation in both cell culture and nude mice xenografts, and drives cells to undergo epithelial to mesenchymal transition (EMT). Our results propose that HSP60 silencing disrupts the integrity of the respiratory complex I and triggers the excessive ROS production, which promotes tumor progression in the following aspects: (1) ROS activates the AMPK pathway that promotes acquisition of the Warburg phenotype in HSP60-KN cells; (2) ROS generated by HSP60 knockdown or by rotenone inhibition drives cells to undergo EMT; and (3) the high level of ROS may also fragment the Fe-S clusters that up regulates ADHFe1 expression and the 2-hydroxygluterate (2-HG) production leading to changes in DNA methylation. These results suggest that the high level of ROS is needed for tumorigenesis and progression in tumors with the low HSP60 expression and HSP60 is a potential diagnostic biomarker as well as a therapeutic target in ccRCC.

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