The dysregulation of androgen receptor (AR) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 (NDRG1) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro. Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 (DNMT1) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.

中文翻译：

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N-cadherin/c-Jun/NDRG1轴在前列腺癌进展中的作用

雄激素受体 ( AR ) 信号的失调是前列腺癌 (PCa) 进展中的一个关键事件，因此由雄激素剥夺 (ADT) 或 AR 抑制组成的激素疗法用于治疗晚期病例。众所周知，ADT 后 N-钙粘蛋白上调，可直接诱导 PCa 转化至去势抵抗期 (CRPC)。然而，AR 和 N-cadherin 之间的关系尚不清楚，可能有助于更好地了解 CRPC 的发病机制和进展。在这里，我们展示了 N-cadherin/c-Jun/N-myc 下游调节基因 1 ( NDRG1) 表明 N-cadherin 促进 c-Jun 表达并抑制 NDRG1 通过上皮间质转化 (EMT) 促进 PCa 细胞的侵袭和迁移。靶向 N-钙粘蛋白与恩杂鲁胺 (ENZ) 联合治疗可在体内和体外协同抑制 PC3 细胞增殖。进一步的研究表明，与较低的 Gleason 评分 (GS) (GS < 7) 病例相比，高 GS (GS > 7) 病例表现出升高的 N-钙粘蛋白表达和降低的 NDRG1 表达，证实了我们的体外观察。我们进一步证明了 c-Jun、AR 和 DNA 甲基转移酶-1 ( DNMT1) 在 NDRG1 启动子的 12-O-十四烷酰基佛波醇-13-乙酸 (TPA) 反应元件 (TRE) 区域形成复合物，通过 DNA 高甲基化抑制 NDRG1 转录。总之，我们展示了 N-cadherin 如何与 AR 和 NDRG1 合作以促进 CRPC 进展的潜在机制。控制 N-cadherin/c-Jun/NDRG1 轴可能有助于克服对常用激素治疗的耐药性，从而改善患者的长期预后。