Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm.NEPC is thought to originate from the trans-differentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/non-coding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drugresistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, microRNAs) play a key role in NEPC initiation and progression. Long non-coding RNAs (lncRNAs) represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively up-regulated in NEPCs and might interact with Polycomb genes. Our results indicate that lncRNAs can be exploited as new biomarkers and therapeutic targets for NEPC.Keywords: Neuroendocrine prostate cancer; MIAT; Long non-coding RNAs; Polycomb; Epigenetic/non-coding interactome; Trans-differentiation. Neuroendocrine Prostate Cancer: Clinical and Molecular FeaturesIn adult males, the prostate is a small acorn-shaped tissue with ductal-acinar histology surrounding the urethra at the base of the bladder. Its main function is to contribute secretory proteins to the seminal fluid [1]. The adult prostate is a pseudo-stratified epithelium composed of three main cell lineages (Fig.1, left panel): 1) secretory luminal cells are the predominant cell type; these cells express keratins (K8, K18), the androgen receptor (AR) and secretory proteins such as prostate-specific antigen (PSA) and prostatic specific acid phosphatase (PSAP);2) basal cells expressing K5 and K14 keratins and p63 are the second major cell type;3) neuroendocrine cells (NEC) expressing chromogranin A (CHGA), synaptophysin (SYP), and neuropeptides are scattered throughout the basal layer and comprise less than 1% of normal prostatic glandular epithelium [1][2][3].Prostate cancer (PCa) represents the second most frequently diagnosed neoplasm and is the sixth leading cause of cancer-related deaths in males worldwide [4,5]. In keeping with the composition of prostate epithelium, more than 95% of PCas are classified as adenocarcinomas, which show luminal phenotype and AR expression [6] (Fig.1, middle panel).Endogenous androgens, mainly produced by the testis, bind to the AR and fuel prostate adenocarcinoma proliferation [7]. For this reason, androgen-deprivation therapy (a.k.a. castration) is an effective therapeutic strategy for this disease. However, patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC) mainly via genetic and epigenetic alterations that facilitate ligand-independent AR activation, amplify the ARdependent signaling, or trigger different proliferative pathways [7]. CRPCs are characterized by substantially worse prognoses, but chemotherapeutics and newly approved hormonal treatments (e.g., Enzalutamide [8] and Abiraterone [9]) are still effective in p...

BackgroundLong non-coding RNAs (lncRNAs) can orchestrate oncogenic or tumor-suppressive functions in cancer biology. Accordingly, PCGEM1 and PRNCR1 were implicated in progression of prostate cancer (PCa) as transcriptional co-regulators of the androgen receptor (AR). However, these findings were recently refuted asserting that neither gene physically binds to the AR. Despite evidence for differing AR transcriptional programs in vivo and in vitro, studies investigating AR-regulation of these genes hitherto have only been conducted in vitro. Here, we further examine the relevance of PCGEM1 and PRNCR1 in PCa, and their relationship with AR signaling, using patient-derived xenograft models.FindingsRNA sequencing of two distinct androgen-dependent models shows PCGEM1 to be considerably expressed, while PRNCR1 showed scant basal expression. PCGEM1 was sharply down-regulated following castration and up-regulated upon AR activation in vivo. However, we found no parallel evidence following AR stimulation in vitro. A PCGEM1-associated gene expression signature (PES) was significantly repressed in response to androgen ablation therapy and in hormone-refractory versus hormone-naïve PCa patients. Furthermore, we found PCGEM1 was uniformly distributed in PCa cell nucleus and cytoplasm which remained unaltered upon AR transcriptional activation. PCGEM1 was up-regulated in primary PCa but not in metastasized PCa. Accordingly, the PES was significantly down-regulated in advanced and higher grade PCa patients from multiple independent studies.ConclusionOur results demonstrate PCGEM1 as an in vivo androgen-regulated transcript with potential nuclear and/or cytoplasmic function(s). Importantly, the clinical expression profile of PCGEM1 implicates it in the early stages of PCa warranting further research in this direction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0314-4) contains supplementary material, which is available to authorized users.

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Carcinoma of the prostate is the most common cancer in men. Treatment of aggressive prostate cancer involves a regiment of radical prostectomy, radiation therapy, chemotherapy and hormonal therapy. Despite significant improvements in the last decade, the treatment of prostate cancer remains unsatisfactory, because a significant fraction of prostate cancers develop resistance to multiple treatments and become incurable. This prompts an urgent need to investigate the molecular mechanisms underlying the evolution of therapy-induced resistance of prostate cancer either in the form of castration-resistant prostate cancer (CRPC) or transdifferentiated neuroendocrine prostate cancer (NEPC). By analyzing micro-RNA expression profiles in a set of patient-derived prostate cancer xenograft tumor lines, we identified miR-100-5p as one of the key molecular components in the initiation and evolution of androgen ablation therapy resistance in prostate cancer. In vitro results showed that miR-100-5p is required for hormone-independent survival and proliferation of prostate cancer cells post androgen ablation. In Silico target predictions revealed that miR-100-5p target genes are involved in key aspects of cancer progression, and are associated with clinical outcome. Our results suggest that mir-100-5p is a possible therapeutic target involved in prostate cancer progression and relapse post androgen ablation therapy.