title: Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma.
abstract: 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.
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Tang
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center of Nephrology, The General Hospital of the PLA, Beijing, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center of Nephrology, The General Hospital of the PLA, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Center of Nephrology, The General Hospital of the PLA, Beijing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D063646:Carcinogenesis; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018834:Chaperonin 60 / Q000378:metabolism*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; C060293:HSPD1 protein, human; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D055372:AMP-Activated Protein Kinases
keywords: HSP60; proteostasis; reactive oxygen species; renal cancer; tumorigenesis