Abstract
BackgroundNext-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression.MethodsTo identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients’ tumor samples.ResultsHere we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion.ConclusionSPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.
Highlights
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations
We demonstrated that SPOP forms a functional CUL3-SPOP-RBX1 E3 ubiquitin ligase complex that targets Activating Transcription Factor 2 (ATF2) for ubiquitination and proteasomal degradation in prostate cancer cells, contributing to facilitating prostate cancer cell migration and invasion
Since the SPOP-ATF2 interaction has not been previously reported in the literature, we examined the potential functional relationship between SPOP and ATF2
Summary
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The most frequently mutated gene in prostate cancer is SPOP (speckle-type POZ protein), which encodes a CULLIN-RING ligases (CRLs) are a family comprised of more than 200 multi-subunit ubiquitin ligase complexes. The CRL3 complex is composed of the scaffold CUL3, the RING protein RBX1, and a BTB (Bric-a-brac/Tramtrack/Broad complex) domain protein that acts as an adaptor for substrate binding. SPOP is a structurally well-characterized BTB protein that interacts with substrates via the MATH domain at its N terminus and binds CUL3 through the BTB domain at its C terminus [8].
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