Proteostasis modulators prolong missense VHL protein activity and halt tumor progression.
Although 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.
Mesh Terms:
Animals, Cell Line, Cell Proliferation, Disease Progression, Gene Expression Regulation, Neoplastic, Half-Life, Histone Deacetylase Inhibitors, Humans, Mice, Mutant Proteins, Mutation, Missense, Neoplasms, Protein Stability, Proteolysis, RNA, Messenger, Von Hippel-Lindau Tumor Suppressor Protein
Animals, Cell Line, Cell Proliferation, Disease Progression, Gene Expression Regulation, Neoplastic, Half-Life, Histone Deacetylase Inhibitors, Humans, Mice, Mutant Proteins, Mutation, Missense, Neoplasms, Protein Stability, Proteolysis, RNA, Messenger, Von Hippel-Lindau Tumor Suppressor Protein
Cell Rep
Date: Jan. 31, 2013
PubMed ID: 23318261
View in: Pubmed Google Scholar
Download Curated Data For This Publication
166266
Switch View:
- Interactions 5