PEG10 is associated with treatment-induced neuroendocrine prostate cancer
PEG10 is associated with treatment-induced neuroendocrine prostate cancer
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DOI：
10.1530/jme-18-0226
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发表时间：
2019-07-01
影响因子：
3.5
通讯作者：
Zoubeidi, Amina
中科院分区：
文献类型：
--
作者：
Kim, Soojin;Thaper, Daksh;Zoubeidi, Amina
晚期前列腺癌在雄激素受体（AR）轴向治疗后的神经内分泌（NE）分化正日益受到重视。这种转分化的几种模型提供了对其分子发病机制的深入了解，并强调了胎盘基因PEG 10的进一步研究。使用我们独特的Enzalutamide耐药（ENZR）和NE分化模型，我们研究了PEG 10/AR在Enzalutamide治疗耐药细胞系42 DENZR和42 FENZR中的相互作用，并与LNCaP和去势耐药16 D（CRPC）细胞进行了比较。与LNCaP和16 D（CRPC）相比，具有阳性末端NE标志物状态的ENZR细胞系也显示出更高的PEG 10基线表达。AR活性的拮抗作用增加了PEG 10表达，随后增加了末端NE标记物。相反，通过雄激素补充刺激AR活性以时间和剂量依赖性方式逆转PEG 10和NE标记物表达。这些结果得到了人类数据的支持，这些数据显示PEG 10在NEPC中表达最高，并且AR依赖性基因PSA与腺癌中的PEG 10呈负相关。此外，ChIP测定证实了活化的AR与PEG 10增强子的结合，降低了PEG 10表达。虽然PEG 10不驱动NEPC，但其敲低减少了我们细胞系中的NE标志物。此外，PEG 10在体外和体内的敲低减弱了肿瘤的生长。总之，这些观察结果表明，PEG 10是一种AR抑制基因，可调节ENZR细胞中的NE标志物，靶向PEG 10治疗具有NE特征的晚期前列腺癌是一种合理可行的选择。
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 16D(CRPC) cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16D(CRPC). 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.