Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found thatLOC730101is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC.
抗雄激素治疗是转移性前列腺癌的标准治疗方案之一。然而，前列腺癌常出现复发，其潜在的耐药机制尚未完全阐明。本研究旨在探讨长链非编码RNA是否参与对新型抗雄激素药物达罗他胺的耐药过程。通过RNA测序分析，我们发现与亲代细胞相比，达罗他胺耐药癌细胞中LOC730101表达显著上调。在临床样本中，转移性去势抵抗性前列腺癌的LOC730101水平也较原发性前列腺癌样本明显升高。利用siRNA沉默LOC730101可显著抑制达罗他胺耐药细胞的生长。进一步的RNA测序分析鉴定出受LOC730101调控的基因集合，其中包括细胞周期调控通路的关键因子。我们证实LOC730101通过竞争性抑制微小RNA miR-1-3p来促进达罗他胺耐药。此外，通过Hi-C测序技术，我们发现LOC730101位于一个拓扑关联结构域内，该结构域在达罗他胺耐药细胞中发生特异性基因诱导。综上所述，本研究揭示了长链非编码RNA LOC730101在达罗他胺耐药中的关键作用，及其作为克服去势抵抗性前列腺癌抗雄激素耐药潜在靶点的重要价值。
LncRNA LOC730101 Promotes Darolutamide Resistance in Prostate Cancer by Suppressing miR-1-3p
肿瘤(癌症)患者之家