Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
J Mol Endocrinol. 2019 Jul 1;63(1):39-49. doi: 10.1530/JME-18-0226.
Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.
神经内分泌（NE）分化在雄激素受体（AR）轴定向治疗后的晚期前列腺腺癌中越来越受到重视。这种转分化的几种模型为其分子发病机制提供了深入了解，并突出了胎盘基因 PEG10 以供进一步研究。使用我们独特的恩扎鲁胺耐药（ENZR）和 NE 分化模型，我们研究了 PEG10/AR 相互作用在恩扎鲁胺治疗耐药细胞系 42DENZR 和 42FENZR 中的作用，与 LNCaP 和去势抵抗的 16DCRPC 细胞相比。具有阳性终末 NE 标志物状态的 ENZR 细胞系也显示出比 LNCaP 和 16DCRPC 更高的 PEG10 基线表达。AR 活性的拮抗作用增加了 PEG10 的表达，随后增加了终末 NE 标志物。相反，通过雄激素补充刺激 AR 活性以时间和剂量依赖的方式逆转了 PEG10 和 NE 标志物的表达。这些结果得到了人类数据的支持，表明 PEG10 在 NEPC 中表达最高，并且 AR 依赖性基因 PSA 在腺癌中与 PEG10 呈负相关。此外，ChIP 测定证实激活的 AR 与 PEG10 增强子结合，降低了 PEG10 的表达。虽然 PEG10 没有驱动 NEPC，但它的敲低减少了我们细胞系中的 NE 标志物。此外，PEG10 在体外和体内的敲低减弱了肿瘤生长。总体而言，这些观察结果表明 PEG10 是一个被 AR 抑制的基因，它调节 ENZR 细胞中的 NE 标志物，针对具有 NE 特征的晚期前列腺癌中的 PEG10 是一种合理且可行的选择。
