VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2

Yao-Hui Gao, Zhao-Xia Wu, Li-Qi Xie, Cai-Xia Li, Yu-Qin Mao, Yan-Tao Duan, Bing Han, San-Feng Han, Yun Yu, Hao-Jie Lu, Peng-Yuan Yang, Tian-Rui Xu, Jing-Lin Xia, Guo-Qiang Chen () and Li-Shun Wang ()
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Yao-Hui Gao: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Zhao-Xia Wu: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Li-Qi Xie: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Cai-Xia Li: Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Yu-Qin Mao: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Yan-Tao Duan: Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Bing Han: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
San-Feng Han: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Yun Yu: Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Hao-Jie Lu: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Peng-Yuan Yang: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Tian-Rui Xu: Faculty of Life Science and Technology, Kunming University of Science and Technology
Jing-Lin Xia: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University
Guo-Qiang Chen: Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Li-Shun Wang: Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract The von Hippel-Lindau (VHL) is deficient in ∼70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of −130 bp to −160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4α). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4α and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.

Date: 2017
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DOI: 10.1038/ncomms15337

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