Role of SPOP in Prostate Cancer
Speckle-Type POZ Protein (SPOP) Mutations Regulate the Steroid Receptor Coactivator-3/Androgen Receptor Axis: A New Pathogenetic Mechanism and Therapeutic Target in Prostate Cancer
Recent exome sequencing studies have identified the E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) as the gene most commonly affected by somatic non-synonymous point mutations in prostate cancer. However, the role of these SPOP mutants in prostate cancer pathophysiology was unknown.
SPOP interacts directly with SRC-3 and promotes its cullin 3 (Cul3)-dependent ubiquitination and proteolysis in breast cancer (Fig. 1), thus functioning as a tumor suppressor (Geng et al. PNAS 2013). SPOP contains two conserved domains: an N-terminal MATH (Meprin and Traf Homology) domain that recruits substrate proteins, and a C-terminal BTB (Bric-a-brac/Tramtrack/Broad complex) domain that interacts with Cul3. All SPOP mutations reported in prostate cancer affect conserved residues in the structurally defined substrate-binding pocket (Fig. 1), raising the hypothesis that they can modify substrate specificity. SPOP mutations comprise an early event in prostate carcinogenesis.
We have now discovered that prostate cancer-associated SPOP mutants cannot interact with SRC-3 protein or promote its degradation (Fig. 1), thus providing a possible explanation of the impact of SPOP mutations in prostate cancer (Geng et al. PNAS 2013). As SRC-3 can potently promote AR transcriptional activity and pleiotropic oncogenic signaling necessary for cancer cell proliferation, survival, metabolism and metastasis, we hypothesized that SRC-3 could be one of the major SPOP substrates mediating the effect of mutant SPOP in prostate cancer and investigated the impact of wild-type and mutant SPOP on SRC expression and function. Overexpression of SPOPWT potently promoted the degradation of SRC-3 protein, but not SRC-1 or SRC-2 protein. All prostate cancer-associated SPOP mutants tested failed to promote SRC-3 ubiquitination and protein degradation. We further documented the physical interaction of SPOPWT with SRC-3 (but not SRC-1 or SRC-2), and this interaction was abolished in these prostate cancer-associated SPOP mutants (Geng et al. PNAS 2013). In prostate cancer cells, SPOPWT suppresses SRC-3 protein expression, cell proliferation and AR transcriptional activity, while this effect is abolished or significantly attenuated by the prostate cancer-associated SPOP mutations.
Our data suggest that wild-type SPOP plays a critical tumor suppressor role in prostate cancer cells, promoting the turnover of SRC-3 protein and suppressing AR transcriptional activity. This tumor suppressor effect is abrogated by the prostate cancer-associated SPOP mutations (Geng et al. PNAS 2013). These studies provide a possible explanation for the role of SPOP mutations in prostate cancer, and highlight the potential of SRC-3 as a therapeutic target in prostate cancer.
- Geng C, He B, Xu L, Barbieri CE, Eedunuri VK, Chew SA, Zimmermann M, Bond R, Shou J, Li C, Blattner M, Lonard DM, Demichelis F, Coarfa C, Rubin MA, Zhou P, O'Malley BW, Mitsiades N. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6997-7002.