Identification of a long non-coding RNA that mediates response to therapy in castration-resistant prostate cancer

Pucci, Perla; Venalainen, Erik; Mather, Rebecca; Xue, Hui; Rigas, Sushila; Romero, Ignacio A; Wang, Yuzho and Crea, Francesco (2017). Identification of a long non-coding RNA that mediates response to therapy in castration-resistant prostate cancer. In: 3rd International Cancer Symposium, 25-27 Sep 2017, Lyon, France.


Prostate cancer (PCa) is the second most commonly diagnosed neoplasm and the sixth leading cause of cancer related death in males, worldwide. It is commonly treated using androgen deprivation therapy, but around 25% of PCas develop resistance to this treatment and are therefore called Castration-Resistant Prostate Cancers (CRPCs). Effective therapies for CRPC include: the second-generation anti-androgen enzalutamide; the taxane cabazitaxel; carboplatin, which is active in androgen receptor negative CRPCs. Nevertheless, response to these therapies is often short-lived making CRPC incurable. Recent evidence suggests that long non-coding RNAs (lncRNAs) can play a role in drug resistance. Using RNA sequencing and qPCR validation, we analysed the expression of lncRNAs in a panel of patient-derived PCa xenografts (PDXs) with opposing sensitivity to castration. Our data showed that HORAS5 was the most consistently up-regulated lncRNA among the CRPC vs. hormone-sensitive PDXs. Moreover, HORAS5 protected CRPC cells from androgen-deprivation induced apoptosis. We next investigated whether HORAS5 had any effect on PCa cells` response to therapies. We analysed the expression and sub-cellular localization of HORAS5 in CRPC cell lines with endogenous or lentiviral-induced expression of HORAS5. CRPC cells were treated with different concentrations of cabazitaxel, carboplatin and enzalutamide. Upon treatment, the expression of HORAS5 was tested via RT-qPCR. Our data showed a significant, dose-dependent increase in HORAS5 expression in cells exposed to cabazitaxel (p<0.01; maximum fold change: 95.07918) and carboplatin (p<0.01; maximum fold change: 71.324). We did not register any significant increase in HORAS5 expression after treatment with enzalutamide. Hence, our results revealed that the expression of HORAS5 can be modulated by two chemotherapeutics in a dose-dependent manner. We are currently evaluating whether HORAS5 silencing affects CRPC cells` response to these drugs. Our data demonstrated that HORAS5 is located mainly in the cytoplasm of PCa cells, and we have predicted that HORAS5 may bind several microRNAs. We therefore hypothesized the involvement of HORAS5 in RNA-induced silencing, where it could act like a competitive endogenous RNA. Our findings suggest that HORAS5 could have a role in CRPC cells` response to therapy. We will further investigate the molecular mechanisms by which HORAS5 drives this phenomenon.

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