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.
Highlights
The von Hippel-Lindau (VHL) is deficient in B70% of clear-cell renal cell carcinomas, which contributes to the carcinogenesis and drug resistance of ccRCC
The results demonstrated that all three anthracycline drugs, but not nonanthracycline chemotherapeutic drugs tested, had higher growth inhibition rates to RCC4/EV than RCC4/VHL cells (Fig. 1b)
The cell growth inhibitory ability of doxorubicin at three different concentrations was always higher in RCC4/EV than in RCC4/VHL cells (Supplementary Fig. 1a)
Summary
The von Hippel-Lindau (VHL) is deficient in B70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. A positive correlation is found among the protein expressions of VHL, HNF-4a and ALDH2 in ccRCC samples These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients. Surgery is the main treatment for this kind of cancer, while RCC is notoriously resistant to conventional chemotherapy, possibly through high expression of some multidrug resistance genes or inactivation of apoptotic pathways[3]. Most of these patients suffer from the side effects of chemotherapy. Whether VHL is a potential therapeutic target for ccRCC is currently unknown
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