Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer–associated mut...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2014-10, Vol.346 (6205), p.85-89
Main Authors: Theurillat, Jean-Philippe P., Udeshi, Namrata D., Errington, Wesley J., Svinkina, Tanya, Baca, Sylvan C., Pop, Marius, Wild, Peter J., Blattner, Mirjam, Groner, Anna C., Rubin, Mark A., Moch, Holger, Privé, Gilbert G., Carr, Steven A., Garraway, Levi A.
Format: Article
Language:English
Subjects:
Cancer
Degradation
Effectors
Genomics
Mutation
Mutations
Prostate
Prostate cancer
Proteins
Proteomics
Substrates
Tumorigenesis
Tumors
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Summary:Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer–associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1250255