Genetic and pharmacological strategies to refunctionalize the von hippel lindau R167Q mutant protein

Zhiyong Ding, Peter German, Shanshan Bai, A. Srinivas Reddy, Xian De Liu, Mianen Sun, Lijun Zhou, Xiaohua Chen, Xiaobei Zhao, Chengbiao Wu, Shuxing Zhang, Gordon B. Mills, Eric Jonasch

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    12 Scopus citations

    Abstract

    Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2a (HIF2a) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2a and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2a. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2a, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations.

    Original languageEnglish (US)
    Pages (from-to)3127-3136
    Number of pages10
    JournalCancer Research
    Volume74
    Issue number11
    DOIs
    StatePublished - Jun 1 2014

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Ding, Z., German, P., Bai, S., Reddy, A. S., Liu, X. D., Sun, M., Zhou, L., Chen, X., Zhao, X., Wu, C., Zhang, S., Mills, G. B., & Jonasch, E. (2014). Genetic and pharmacological strategies to refunctionalize the von hippel lindau R167Q mutant protein. Cancer Research, 74(11), 3127-3136. https://doi.org/10.1158/0008-5472.CAN-13-3213