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Androgen receptor (AR) activation is critical for prostate cancer development and progression, including castration-resistance. The nuclear export signal of AR (NESAR) plays an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in prostate cancer specimens and its expression was correlated with Gleason scores and PSA recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to prostate cancer progression through Siah2.

BackgroundProstate cancer is one of the most common malignancies. Increasing evidence suggested that endothelial cells may contribute to prostate cancer progression and metastasis. Most recently, autophagy has been proposed to plays a significant role in tumorigenesis and metastasis. Also, it is reported that downregulation of androgen receptor (AR) induces autophagy in prostate cancer cells. However, the underlying mechanisms remain unclear. Here, we aim to explore the role and mechanisms of endothelial cell in prostate cancer progression.MethodsThe coculture system was established to test the effect of endothelial cells on prostate cancer cells. We performed antibody array and ELISA were used to profile the cytokine expression pattern of endothelial cells in supernatant. Western blot and RT-PCR were used to determine the mechanism by endothelial cells to promote invasion ability of prostate cancer cells. Maraviroc and chloroquine were used to block the CCL5/CCR5 and autophagy pathway respectively. Orthotopic xenograft mouse models and drug treatment study were conducted to determine the role of endothelial cells in promoting metastatic potential in vivo.ResultsWe use CPRC prostate cancer model and demonstrate that endothelial cells secrete large amount of CCL5 and induces autophagy by suppressing AR expression in prostate cancer cell lines. Consequently, elevated autophagy accelerates focal adhesions proteins disassembly and promoted prostate cancer invasion. Inhibition of both CCL5/CCR5 signaling and autophagy significantly reduces metastasis in vivo.ConclusionsTogether, our data establish the function for endothelial cells in tumor metastasis and propose new drug target for mCRPC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0884-2) contains supplementary material, which is available to authorized users.

Micturition remained stable after TmLRP-TT during the 4-year follow-up. Outcomes compared favourably with TURP, with lower peri-operative morbidity and equally low occurrence of late adverse effects. Thus, TmLRP-TT can be an available option for BPH patients, especially older, high-risk patients.

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Thulium laser resection of the prostate is a safe and effective procedure with excellent durability in the treatment of symptomatic BPH.

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Summary The epidermal hair and stomata are two types of specialized structures on the surface of plant leaves. On mature maize leaves, stomatal complexes and three types of hairs are distributed in a stereotyped pattern on the adaxial epidermis. However, the spatiotemporal relationship between epidermal hair and stomata development and the regulatory mechanisms governing their formation in maize remain largely unknown. Here, we report that three homologous ZmSPL transcription factors, ZmSPL10, ZmSPL14 and ZmSPL26, act in concert to promote epidermal hair fate on maize leaf. Cytological analyses revealed that Zmspl10/14/26 triple mutants are completely glabrous, but possess ectopic stomatal files. Strikingly, the precursor cells for prickle and bicellular hairs are transdifferentiated into ectopic stomatal complexes in the Zmspl10/14/26 mutants. Molecular analyses demonstrated that ZmSPL10/14/26 bind directly to the promoter of a WUSCHEL‐related homeobox gene, ZmWOX3A, and upregulate its expression in the hair precursor cells. Moreover, several auxin‐related genes are downregulated in the Zmspl10/14/26 triple mutants. Our results suggest that ZmSPL10/14/26 play a key role in promoting epidermal hair fate on maize leaves, possibly through regulating ZmWOX3A and auxin‐related gene expression, and that the fates of epidermal hairs and stomata are switchable.