Abstract
SPOP mutations enhance tumorigenesis by disrupting the ubiquitylation of substrates such as DEK.
Major finding: SPOP mutations enhance tumorigenesis by disrupting the ubiquitylation of substrates such as DEK.
Mechanism: Mutant SPOP functions as a dominant-negative by forming heteromeric complexes with wild-type SPOP.
Impact: Ubiquitylome changes induced by cancer-associated mutations identify mechanisms of tumorigenesis.
Cancer genome sequencing has identified mutations in components of the ubiquitylation machinery, but the contribution of these alterations to tumorigenesis is not yet fully understood. Theurillat, Udeshi, Errington, and colleagues assessed the role of changes in the ubiquitin landscape induced by mutations in speckle-type POZ protein (SPOP), which encodes an E3 ubiquitin ligase adaptor protein, in prostate cancer. Characterization of the ubiquitylome of immortalized prostate epithelial cells expressing wild-type SPOP or one of two prostate cancer–associated SPOP mutants revealed a decrease in ubiquitylated peptides from five proteins in response to mutant SPOP, of which the putative oncoprotein DEK also exhibited marked increases in total protein levels, suggesting that SPOP mutations impair DEK degradation. Consistent with this idea, forced expression of wild-type SPOP decreased DEK protein levels, whereas expression of mutant SPOP resulted in reduced degradation and accumulation of DEK protein. In addition, mutation of the consensus SPOP-binding motif in DEK or expression of mutant SPOP disrupted the interaction of DEK with SPOP and suppressed DEK ubiquitylation and proteasome-mediated degradation, confirming DEK as an SPOP substrate. Prostate cancer–associated SPOP mutants repressed the regulation of DEK by wild-type SPOP in a dominant-negative manner via formation of heteromeric complexes with wild-type SPOP. Further, expression of prostate cancer–associated mutant SPOP promoted oncogenic phenotypes, including enhanced prostate epithelial cell invasion and maintenance of stem cell–like properties, in a DEK-dependent manner. Moreover, nuclear accumulation of DEK and a subset of other potential SPOP substrates correlated with SPOP mutations in human prostate cancer samples, indicating a potential role for dysregulation of SPOP-mediated substrate degradation in prostate cancer transformation. Taken together, these findings support large-scale profiling of the ubiquitin landscape as a useful tool to elucidate the mechanisms by which mutations in regulators of protein homeostasis promote tumorigenesis.
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