Dutta Samikshan, Bhattacharya Sreyashi, Harris Hanna, Islam Ridwan, Bodas Sanika, Polavaram Navatha, Mishra Juhi, Das Dipanwita, Seshacharyulu Parthasarathy, Kalluchi Achyuth, Pal Anirban, Kohli Manish, Lele Subodh, Muders Michael, Batra Surinder, Ghosh Paramita, Datta Kaustubh, Rowley Michael
UNMC.
University of Utah.
Res Sq. 2023 Dec 11:rs.3.rs-3464475. doi: 10.21203/rs.3.rs-3464475/v1.
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 cellular interaction in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to taxane 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.
对当前雄激素受体信号抑制剂（ARSI）疗法产生耐药性导致治疗诱导的神经内分泌样前列腺癌（t-NEPC）的发病率升高。这种具有主要小细胞样特征的高度侵袭性亚型对紫杉烷化疗耐药，总体生存率不佳。t-NEPC大多采用铂类药物联合依托泊苷或紫杉烷进行治疗，其选择性较低且全身毒性高，这常常限制了它们的临床应用潜力。在t-NEPC转化过程中，腺癌失去其管腔特征并呈现神经基底特征。t-NEPC的适应性神经元特征是否导致这种紫杉烷耐药性尚不清楚。来自患者基因表达数据库的通路分析表明，t-NEPC上调了与增强细胞网络相关的各种神经元通路。为了鉴定对促进t-NEPC中神经元特征基因表达可能重要的转录因子（TF），我们在我们的神经内分泌样细胞系模型中进行了ATAC测序、乙酰化组蛋白ChIP测序和RNA测序，并分析了转录活跃且显著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，且对t-NEPC具有特异性。通路分析显示，Pax5表达参与轴突导向、神经递质调节和神经元黏附，这些对于强大的细胞通讯至关重要。进一步的结果表明，Pax5的缺失破坏了神经内分泌样细胞中的细胞相互作用并降低了表面生长因子受体的激活，从而使它们对紫杉烷疗法敏感。此外，t-NEPC中Pax5启动子CpG岛的特异性羟甲基化有利于Pbx1结合以诱导Pax5表达。基于我们的研究，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，这促进了采用紫杉烷耐药性神经内分泌样癌症所需基因的表达。因此，靶向Pax5轴可能有利于恢复它们对紫杉烷的敏感性。
