Prostate cancer. 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 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.
Mesh Terms:
Base Sequence, Binding Sites, Carcinogenesis, Carrier Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Invasiveness, Nuclear Proteins, Oncogene Proteins, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Repressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Base Sequence, Binding Sites, Carcinogenesis, Carrier Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Invasiveness, Nuclear Proteins, Oncogene Proteins, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Repressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Science
Date: Oct. 03, 2014
PubMed ID: 25278611
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