The Mechanistic Role of Long Non-coding RNAs in Advanced Prostate Cancer Response to Therapy

Pucci, Perla (2020). The Mechanistic Role of Long Non-coding RNAs in Advanced Prostate Cancer Response to Therapy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000111da

Abstract

Prostate cancer is one of the most common malignancies and the fifth leading cause of cancer related deaths in males, worldwide. It is commonly treated using androgen deprivation therapy (ADT), but around 25% develop ADT resistance and are called Castration-Resistant Prostate Cancers (CRPCs). Therapies currently used for CRPC treatment include: the new generation anti-androgen enzalutamide, the taxane cabazitaxel and carboplatin. Despite the prolonged survival resulting from these treatments, CRPC is still incurable. Recent evidence suggests that long non-coding RNAs (lncRNAs) promote drug resistance. The lncRNA HORAS5 (i.e. linc00161) regulates drug response in different cancers and is upregulated in CRPC versus hormone-sensitive patient-derived xenografts (PDXs), thereby stimulating pro-survival mechanisms. This project has investigated whether HORAS5 has a role in CRPC response to therapy. CRPC cells have been treated with different concentrations of cabazitaxel, carboplatin and enzalutamide. Cabazitaxel exposure increases HORAS5 expression, in androgen receptor-positive (AR+) and -negative (AR–) prostate cancer cells and HORAS5 overexpression decreases cabazitaxel sensitivity and cell apoptosis. HORAS5 RNA interference (RNAi) increases cabazitaxel sensitivity and cell apoptosis. Next-generation RNA sequencing and real time qPCR have shown that the anti-apoptotic factor BCL2A1 is significantly upregulated upon HORAS5 overexpression in AR- prostate cancer cells exposed to cabazitaxel. BCL2A1 silencing decreases cell count and increases apoptosis of prostate cancer cells exposed to cabazitaxel. HORAS5 and BCL2A1 upregulation is associated with decreased survival in prostate cancer patients and HORAS5 is upregulated in clinical samples from prostate cancer patients exposed to taxanes. Transfection of CRPC cells with HORAS5-targeting antisense oligonucleotides (ASOs) efficiently reduces HORAS5 expression, thereby decreasing cabazitaxel IC₅₀ when tested in combination with this drug. Overall, this project shows that HORAS5 stimulates BCL2A1 expression in prostate cancer cells, thereby reducing caspase-mediated apoptosis. This leads to increased cabazitaxel resistance. The clinical relevance of HORAS5 expression and the effect of HORAS5-targeting ASOs shown in this thesis highlight the translational potential of HORAS5 modulation. This work sheds light on the relevance of lncRNAs in cancer drug resistance and proposes the use of HORAS5 as a future therapeutic target to increase therapy efficacy in CRPC.

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