Abstract
SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG. SPOP mutations and TMPRSS2-ERG rearrangements are two of the most prevalent genetic alterations in human prostate cancer. An et al. report that SPOP functions as a tumor suppressor in prostatic cells by promoting ERG degradation, but this function is abrogated by both SPOP mutations and the majority of TMPRSS2-ERG fusions.
Original language | English (US) |
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Pages (from-to) | 904-916 |
Number of pages | 13 |
Journal | Molecular Cell |
Volume | 59 |
Issue number | 6 |
DOIs | |
State | Published - Sep 17 2015 |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology