LncRNA HORAS5 promotes taxane resistance in castration-resistant prostate cancer via a BCL2A1-dependent mechanism.

Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i. e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion:HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.

Epigenomics. 2020 Jul 03 [Epub ahead of print]

Perla Pucci, Erik Venalainen, Ilaria Alborelli, Luca Quagliata, Cheryl Hawkes, Rebecca Mather, Ignacio Romero, Sushilaben H Rigas, Yuzhuo Wang, Francesco Crea

School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, MK7 6AA, UK., Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada., Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland., Global Head of Medical Affairs, Clinical NGS & Oncology Division, Life Sciences Solutions, Thermo Fisher Scientific, Baarerstrasse, Switzerland.