Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression

SummaryAlthough missense mutations of the von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown. We found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physiologic mRNA expression. Although mutant pVHL is unstable and degraded contemporarily with translation, it retains its E3 ligase function, including hypoxia-inducible factor degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding. Histone deacetylase inhibitors (HDACIs) can modulate this pathway by inhibiting the HDAC-Hsp90 chaperone axis, stabilizing pVHL, and restoring activity comparable to wild-type protein, both in vitro and in animal models. Furthermore, HDACI-mediated stabilization of missense pVHL significantly attenuates the growth of 786-O rodent tumor model. These findings provide direct biological insight into VHL-associated tumors and elucidate a treatment paradigm for VHL.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Loss of mutant pVHL in VHL-associated tumors is due to rapid degradation ► Mutant pVHL maintains its intrinsic function as an E3 ligase ► HDACIs stabilize mutant pVHL and ameliorate tumor growth in vivo ► HDACIs represent a targeted therapy for VHL-associated tumors