Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15337
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Funding
- National Natural Science Foundation of China [81472758, U1302225, 31170783, 81230048]
- Science and Technology Commission of China [2015CB910403]
- Science and Technology Commission of Shanghai [E09013, SKLGE-1510, 14ZR1436400, 2016MHZ34]
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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. 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-4 alpha). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4 alpha and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.
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