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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehyde Dehydrogenase, Mitochondrial / genetics*
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Aldehyde Dehydrogenase, Mitochondrial / metabolism
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Animals
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Anthracyclines / pharmacology
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Anthracyclines / therapeutic use*
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Anthracyclines / toxicity
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / genetics*
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Carcinoma, Renal Cell / pathology
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Cell Death / drug effects
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Cell Line, Tumor
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Down-Regulation / drug effects
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Down-Regulation / genetics*
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Gene Expression Regulation, Neoplastic / drug effects
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Hepatocyte Nuclear Factor 4 / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / pathology
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Male
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Mice, Nude
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Neoplasm Proteins / metabolism
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Proteomics
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Transcription, Genetic / drug effects
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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Anthracyclines
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HIF1A protein, human
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HNF4A protein, human
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Hepatocyte Nuclear Factor 4
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Hypoxia-Inducible Factor 1, alpha Subunit
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Neoplasm Proteins
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ALDH2 protein, human
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Aldehyde Dehydrogenase, Mitochondrial
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human