Prostate cancer ( PC a) is driven by the androgen receptor ( AR )‐signaling axis. Hormonal therapy often mitigates PC a progression, but a notable number of cases progress to castration‐resistant PC a ( CRPC ). CRPC retains AR activity and is incurable. Long noncoding RNA (lnc RNA ) represent an uncharted region of the transcriptome. Several lnc RNA have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC ‐associated lnc RNA by analyzing patient‐derived xenografts ( PDX s) and clinical data. Subsequently, we characterized one of the CRPC ‐promoting lnc RNA , HORAS 5 , in vitro and in vivo . We demonstrated that HORAS 5 is a stable, cytoplasmic lnc RNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen‐depleted conditions. Most strikingly, knockdown of HORAS 5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA 0101. Elevated expression of HORAS 5 is also associated with worse clinical outcomes in patients. Our results from HORAS 5 inhibition in in vivo models further confirm that HORAS 5 is a viable therapeutic target for CRPC . Thus, we posit that HORAS 5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lnc RNA function in cancer progression.

Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease-and tissue-specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor-matched patient-derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR + /PSA + ) or NEPC (AR À /SYN + /CHGA + ) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229-fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC-3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell

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Soluble-Mesothelin Related Peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hamper its usefulness in surveillance programs. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of mesothelin (MSLN) gene could affect the levels of SMRP. Here, we focused on SNPs located within MSLN promoter and found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (that is in strong linkage disequilibrium with rs2235504), and rs2235503 in non-MPM subjects. The inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the MPM population showed the same trend of association. In order to study the biological role of these SNPs, the promoter region of MSLN was cloned upstream a reporter gene and the four most common haplotypes were compared in a dual luciferase assay. Rs3764247 was shown to have a functional role itself. The other SNPs were shown to interact with each other in a more complex way. Altogether, these data support the idea that SMRP performance is affected by individual (i.e. genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.

Background Androgen deprivation therapy (ADT) is the treatment of choice for metastatic prostate cancer (PCa). After an initial response to ADT, PCa cells can generate castration resistant (CRPC) or neuroendocrine (NEPC) malignancies, which are incurable. T‐type calcium channels (TTCCs) are emerging as promising therapeutic targets for several cancers, but their role in PCa progression has never been investigated. Methods To examine the role of TTCCs in PCa, we analyzed their expression level, copy number variants (CNV) and prognostic significance using clinical datasets (Oncomine and cBioPortal). We then evaluated TTCC expression in a panel of PCa cell lines and measured the effect of their inhibition on cell proliferation and survival using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and caspase assays. Results TTCCs were upregulated in PCas harboring androgen receptor (AR) mutations; CNV rate was positively associated with PCa progression. Higher expression of one TTCC isoform (CACNA1G) predicted poorer postoperative prognosis in early stage PCa samples. Pharmacological or small interfering RNA (siRNA)‐based inhibition of TTCCs caused a decrease in PC‐3 cell survival and proliferation. Conclusions Our results show that TTCCs are overexpressed in advanced forms of PCa and correlate with a poorer prognosis. TTCC inhibition reduces cell proliferation and survival, suggesting that there may be possible value in the therapeutic targeting of TTCCs in advanced PCa.