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10.1158/0008-5472.CAN-14-0476

http://scihub22266oqcxt.onion/10.1158/0008-5472.CAN-14-0476
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C4209379!4209379!25274033
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suck abstract from ncbi


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pmid25274033      Cancer+Res 2014 ; 74 (19): 5631-43
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  • Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer #MMPMID25274033
  • Geng C; Rajapakshe K; Shah SS; Shou J; Eedunuri VK; Foley C; Fiskus W; Rajendran M; Chew SA; Zimmermann M; Bond R; He B; Coarfa C; Mitsiades N
  • Cancer Res 2014[Oct]; 74 (19): 5631-43 PMID25274033show ga
  • Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas (PC), but are rare in other malignancies suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator factor SRC-3. However, the relative contributions that SPOP substrates may contribute to the pathophysiology of SPOP-mutant (mt) PC is unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of PC cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger effect on AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR mediated. Indeed, we found that wild-type (wt) but not PC-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of PC cells expressing mt-SPOP expressed higher AR protein levels and grew faster than tumors composed of PC cells expressing wt-SPOP. Further, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human PC datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in PC, and they provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.
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