LncRNA HORAS5 Promotes Taxane Resistance in Castration-Resistant Prostate Cancer via a BCL2A1-Dependent Mechanism

Abstract

<jats:p> Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials &amp; methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC<jats:sub>50</jats:sub> 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 IC<jats:sub>50</jats:sub>. 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. </jats:p>

Mechanisms of Taxane Resistance

“…This suggests that CBZ stimulates the overexpression of HORAS5 or that the cells overexpressing HORAS5 are more primed to survive increasing concentrations of CBZ. Knockdown of HORAS5 confirmed the role in CBZ response, which demonstrated a CBZ concentration-dependent increase in growth inhibition [443]. Because there are so many lncRNAs that have different target pathways, using one specific inhibitor or ASO may not be the best approach to prevent or fight resistance, but monitoring levels of pro-survival lncRNAs could be used as a biomarker for patient response to taxanes.…”

“…HOXD-AS1 correlates with response to taxanes by utilizing WD repeat domain 5 (WDR5) to act as the direct regulator of target genes such as PLK1, AURKA, CDC25C, UBE2C, and FOXM1, which all play roles in continuing the cell cycle [440][441][442]. Lastly, the lncRNA HORAS5 is associated with cell proliferation in CRPC and HORAS5-overexpressing cells decreased growth inhibition by CBZ treatment in a dose-dependent manner [443]. This suggests that CBZ stimulates the overexpression of HORAS5 or that the cells overexpressing HORAS5 are more primed to survive increasing concentrations of CBZ.…”

LncRNA Polymorphism Affects the Prognosis of Gastric Cancer

“…LncRNA is an important class of non-coding RNA with a potential carcinogenic role affecting cell proliferation and apoptosis [17][18][19][20]. It can also affect the prognosis of cancer by acting on key signaling pathways and alter the invasiveness of cancer cells [21][22][23][24]. In this study, we deeply explored the relationship between lncRNA polymorphisms and GC prognosis.…”

Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

“…Dysregulation of lncRNAs is a common phenomenon in cancer due to their role in regulating important biological processes [ 281 ]. In prostate cancer, lncRNAs can regulate lymph node metastasis, proliferation, and therapy response via affecting different molecular pathways, especially miRNAs [ 282 – 284 ]. In this section, the role of lncRNAs in regulating autophagy and affecting prostate cancer progression is discussed.…”