The ubiquitin ligase Siah2 is revealed as an accomplice of the androgen receptor in castration resistant prostate cancer

The androgen receptor （AR） remains the primary molecular target forprostate cancer （PCa） treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown that the AR is still functional during latestage disease in the absence of circulating hormone fol lowing castration therapy. The molecular mechanisms that operate during this ＇cas tration resistant＇ phase are still not well understood. Qi et al. have now implicated the ubiquitin ligase Siah2 as an important mediator of AR action in castration resis tant prostate cancer （CRPC）. Siah2 was found to target repressed AR chromatin complexes for degradation, resulting in activation of ARregulated genes involved in tumor cell proliferation, cell motility and lipid metabolism. The authors show a requirement for Siah2 activity for PCa cell growth under conditions of low androgen, and also that targeting Siah2 results in tumor growth suppression under castrate conditions. These findings identify a new mechanism of AR regulation in progressing disease as well as a novel enzymatic target for therapeutic intervention. The AR is a wellstudied hormone receptor that belongs to the large nuclear receptor gene superfamily. AR is activated by androgen binding （principally 5：~dihydrotestosterone, 5DHT）, which elicits changes in AR resident cytosolic complexes, translocation of the receptor to cell nuclei, formation of multiprotein transcriptional complexes onchromatin, and activation or repression of gene expression. Experiments with in vivo model systems have provided evidence that virtually all physiologic processes affected by androgens require the AR as a mediator of molecular effects at the gene level.1 AR is widely expressed beyond the reproductive systems and is believed to play important roles in several nonreproductive tissues, including muscle and brain. The fact that PCa growth is initially dependent on the pre sence of androgens in the circulation, and that prostate tumors will regress temporarily with castration, has been recognized for over half a century. Molecular cloning was initially felt to of the AR in the 1980s be a dispositive step toward pharmacological interventions that would greatly improve treatment outcomes for PCa. However, despite many advances since that time, there is currently no effec tive therapy for disease that has become unresponsive to treatment with hormone ablation. The ＇hormone refractory＇ phase of the disease is intriguing from a bioche mical perspective because the AR still appears to play a critical role under conditions where androgen concentrations in the blood are extremely low. RNA and gene profiling of many human PCa tumors has shown that hormone suppression provides a strong selec tion pressure that results in overexpression and/or amplification of the AR during meta static dissemination.2 Molecular and bio chemical studies of the AR have revealed a bewildering level of complexity involving over 150 protein partners. The AR is also posttranslationally modified by phosphory lation, sumoylation and acetylation, and AR expression can be controlled at transcrip tional and posttranscriptional levels, adding additional layers of regulatory complexity. One important locus of AR activity lies in the ubiquitin/proteasome pathway, which controls the specificity and rate of protein degradation. AR stability was shown pre viously to be regulated by ubiquitin ligases,3 proteins that form complexes with ubiquitin conjugating enzymes to catalyze attachment of the small protein ubiquitin to lysines on a protein target, thereby directing the modified protein to the proteasome for degradation. Siahl and Siah2 are RING finger E3 ubiquitin ligases that regulate ubiquitinationmediated degradation of a range of signaling proteins, resulting in diverse biological effects such as resistance to apoptosis and effects on mito chondrial function. Qi et al.4 previously showed that knockout of the Siah2 gene in the TRAMP transgenic mouse model of PCa, a system that rapidly produces aggres sive autochthonous prostate tumors that pro gress to metastasis, resulted in suppression of tumor formation. In a recent paper in Cancer Cell,5 the same group has now gone on to uncover the mechanism of this surprising effect. Further experiments in TRAMP mice indi cated that loss of Siah2 decreased prostate size, an indication of a loss of AR signaling, and also increased the sensitivity to castra tion, suggesting the possibility that Siah2 may operate under low androgen conditions. Knockdown of Siah2 in PCa cell lines indi cated that Siah2 controls a subset of AR regulated genes, including the gene encoding the important clinical biomarker, prostate specific antigen. Global transcriptional profi ling identified a Siah2regulated gene network consisting of almost 1000 genes, about 100 of which were found to be AR regulated. The AR and Siah2dependent genes were mostly associated with lipid, sterol and cholesterol metabolism. Analysis of human PCa profiling

Trading in your spindles for blebs： the amoeboid tumor cell phenotype in prostate cancer

Prostate cancer （PCa） remains a principal cause ofmortalityin developed countries.Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor ceils reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ＇amoeboid＇ phenotype is increasingly appreciated as relevant to human cancer.