Renal cell carcinoma (RCC) is the most common malignant kidney tumors in adults. Von Hippel-Lindau (VHL) gene is deficient in >50% of RCC cases, but the role of VHL as a potential therapeutic target in RCC has not been well established. In the present study, 9-cis-Retinoic acid, which is a potent natural agonist of retinoid X receptors (RXRs), was found to decrease the viability of VHL-proficient RCC cells, but had little effect on VHL-deficient RCC cells. In addition, it was demonstrated that VHL transcriptionally regulated RXR alpha in a hypoxia-inducible factor-alpha independent manner. Moreover, a negative correlation was observed between the expressions of VHL and RXR alpha in RCC tissues. Collectively, these data indicate that VHL-proficient RCC patients may be more sensitive to treatment with 9-cis-retinoic acid, which acts by regulating RXR alpha expression, compared with VHL-deficient RCC patients. The findings of the present study demonstrate a novel function of VHL and highlight the potential of VHL expression as a therapeutic modality for the optimized treatment of RCC patients. (C) 2020 Elsevier Inc. All rights reserved.