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<p>Prostate cancer is (PCa) the second leading cause of cancer death in males in the United State, with 174,650 new cases and 31,620 deaths estimated in 2019. Polo-like kinase 1 (PLK1) has been postulated to have a pro-tumorigenesis function, besides its critical role in regulation of cell cycle, and to be overexpressed in various types of human cancer, including prostate cancer (PCa). However, our understanding remains unclear regarding the pro-tumor properties of PLK1 partially due to a lack of proper animal model. Integrating our recently generated prostate-specific PLK1 knock-in genetically engineered mouse model (GEM) and the transcriptome data of human PCa patients, we identify an oncogenic role of PLK1 in the prostate adenocarcinoma progression, castration resistance and metastatic dissemination. To elucidate the underlying mechanism, we investigate the link between PLK1 and tumor microenvironment in PCa using the transgenic mouse model, and find that PLK1overexpression enable the macrophages polarization towards M2 phenotype via driving the activation of IL4/IL13/STAT6 pathway. These findings first validates PLK1 as a critical oncogene closely associated with PCa progression in vivo, and uncover a novel function of PLK1 to facilitate IL4/STAT6 signaling and M2 macrophage polarization. Importantly, these findings suggest an efficient therapeutic strategy targeting STAT6 for treatment of advanced PCa which usually possessing a high level of PLK1 expression. To further explore the molecular mechanism underlying PLK1-induced PCa progression and resistance to therapy, we turned our eyes to epigenetic modifications. It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression. Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb-repressive complex 2 (PRC2), plays a critical role in repressing gene expression by tri-methylation of histone 3 at lysine 27 (H3K27me3). Emerging data have demonstrated that there is a link between EZH2 and oncogenesis as EZH2-mediated methylation acts as an important factor in epigenetic silencing of tumor suppressor genes in cancer. Expression of EZH2 is often upregulated in castration-resistant prestate cancer (CRPC), thus EZH2 has been proposed as a target for CRPC. Importantly, it has been demonstrated that EZH2 becomes hyperphosphorylated in CPRC cells. Further, it has been shown that the oncogenic function of EZH2 is usually regulated by the post-translational modifications. PLK1 acting as a serine/threonine kinase to regulate multiple signaling pathways in human cancer, however, whether PLK1 is involved in EZH2 phosphorylation is not known. Herein, we show that Plk1 physically interacts with EZH2 and negatively regulates H3K27 trimethylation (H3K27me3). Furthermore, Plk1 can phosphorylate EZH2 at T144, and Plk1-mediated phosphorylation of EZH2 is involved in inhibiting EZH2 activity toward H3K27me3. More importantly, EZH2 phosphorylation by Plk1 is inhibitory for PRC2-mediated gene repression but required for transcriptional activation toward oncogenesis. Finally, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of EZH2 inhibitors in CRPC cell lines, as well as in CRPC xenograft tumors. Our findings provide a new mechanism to define the oncogenic activity of EZH2 and suggest that inhibition of Plk1-mediated EZH2 activity may provide a promising therapeutic approach for CRPC.</p>

Yes / The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data. / University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.