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Medicine - Mitsiades Lab

Houston, Texas

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Medicine - Mitsiades Lab
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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.


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