对当前雄激素受体信号抑制剂（ARSI）疗法的耐药性导致治疗诱发的神经内分泌样前列腺癌（t-NEPC）的发病率更高。这种高度侵袭性的亚型具有主要的小细胞样特征，对紫杉烷化疗有抵抗力，并且总体生存率很低。 t-NEPCs大多采用铂类药物联合依托泊苷或紫杉烷进行治疗，选择性较低且全身毒性较高，这往往限制了其临床潜力。在 t-NEPC 转化过程中，腺癌失去其管腔特征并采用神经基底特征。 t-NEPC 的适应性神经元特征是否导致这种紫杉烷耐药性仍不清楚。患者基因表达数据库的通路分析表明，t-NEPC 上调与增强的细胞网络相关的各种神经元通路。为了鉴定对促进 t-NEPC 神经元特征基因表达可能重要的转录因子 (TF)，我们在 NE 样细胞中进行了 ATAC-Seq、乙酰化组蛋白 ChIP-seq 和 RNA-seq线模型并分析了转录活性和显着富集的神经内分泌样（NE样）癌症特异性基因的启动子。我们的结果表明 Pax5 可能是神经元基因表达的重要转录因子，并且对 t-NEPC 具有特异性。通路分析显示 Pax5 表达参与轴突引导、神经递质调节和神经元粘附，这对于强大的细胞通讯至关重要。进一步的结果表明，Pax5 的耗竭会破坏 NE 样细胞中神经突介导的细胞通讯，并减少表面生长因子受体的激活，从而使它们对多西紫杉醇疗法敏感。此外，Pax5启动子CpG岛的t-NEPC特异性羟甲基化有利于Pbx1结合以诱导Pax5表达。根据我们的研究，我们得出结论，持续暴露于 ARSI 疗法会导致 t-NEPC 中的表观遗传修饰和 Pax5 激活，从而促进采用紫杉烷抗性 NE 样癌症所需的基因表达。因此，针对 Pax5 轴可能有利于恢复其紫杉烷敏感性。© 2024。作者。

Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small-cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts neurite-mediated cellular communication in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to docetaxel therapies. Moreover, t-NEPC-specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.© 2024. The Author(s).