The majority of patients with prostate cancer treated with docetaxel develop resistance to it. To better understand the mechanism behind the acquisition of resistance, we conducted single-cell RNA-sequencing (scRNA-seq) of docetaxel-sensitive and -resistant variants of DU145 and PC3 prostate cancer cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both prostate cancer cell lines. A subset of these genes gave a gene expression profile in the resistant transcriptome-like–sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified 321 potential regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single-cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the prostate cancer cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of scRNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of prostate cancer drug resistance, which provides the rationale to explore NUPR1 and its target genes for reversal of docetaxel resistance. Implications: Using single-cell sequencing of prostate cancer, we show that NUPR1 plays a role in docetaxel resistance.

中文翻译：

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单细胞转录组学分析将核蛋白 1 鉴定为前列腺癌细胞中多西紫杉醇耐药性的调节剂

大多数接受多西紫杉醇治疗的前列腺癌患者对其产生耐药性。为了更好地了解获得耐药性背后的机制，我们对 DU145 和 PC3 前列腺癌细胞系的多西紫杉醇敏感和耐药变体进行了单细胞 RNA 测序 (scRNA-seq)。总体而言，敏感和抗性细胞分别聚集。耐药细胞和敏感细胞之间的差异基因表达分析揭示了两种前列腺癌细胞系共有的 182 个差异表达基因。这些基因的一个子集在类似于抗性细胞的抗性转录组样敏感细胞中提供了基因表达谱。对功能基因通路的探索确定了两种细胞系之间的 218 条共同通路。蛋白质泛素化是差异最大的调节途径，并在抗性细胞中富集。转录调节器分析确定了两种细胞系中的 321 个潜在调节器。确定的顶级调节因子之一是核蛋白 1 (NUPR1)。与单细胞分析相反，细胞的批量分析并未显示 NUPR1 作为有希望的候选者。前列腺癌细胞中 NUPR1 的敲低和过表达表明 NUPR1 在两种细胞系中都具有多西紫杉醇抗性。总的来说，这些数据证明了 scRNA-seq 在识别耐药性调节因子方面的效用。此外，NUPR1 被确定为前列腺癌耐药性的介质，这为探索 NUPR1 及其靶基因逆转多西紫杉醇耐药性提供了理论依据。含义：