SOX9 drives WNT pathway activation in prostate cancer
SOX9 drives WNT pathway activation in prostate cancer
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DOI：
10.1172/jci78815
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发表时间：
2016-05-01
影响因子：
15.9
通讯作者：
Yuan, Xin
中科院分区：
文献类型：
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作者：
Ma, Fen;Ye, Huihui;Yuan, Xin
转录因子SOX9对前列腺发育至关重要，SOX9的失调与前列腺癌（PCa）有关。然而，在正常和肿瘤前列腺上皮中涉及的sox9依赖基因和途径在很大程度上是未知的。在此，我们对PCa细胞进行了SOX9 ChIP测序分析和转录组分析，确定SOX9正调控多个WNT通路基因，包括编码WNT受体的基因（卷曲[FZD]和脂蛋白受体相关蛋白[LRP]家族成员）和下游β -连环蛋白效应物TCF4。对PCa异种移植和临床样本的分析均显示，SOX9和WNT通路成分在PCa中的表达存在关联。最后，用WNT合成抑制剂（LGK974）处理表达sox9的PCa细胞，可以减少体外WNT通路信号传导和小鼠异种移植模型中的肿瘤生长。总之，我们的数据表明，SOX9表达通过重新激活介导胎儿前列腺导管形态发生的WNT/ β -连环蛋白信号来驱动PCa，并确定了一个亚组患者将受益于WNT靶向治疗。
The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream beta-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/beta-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy.