Department of Pathology, Shandong University Medical School, Jinan, China; Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan, China.
Prostate. 2014 May;74(6):647-58. doi: 10.1002/pros.22783. Epub 2014 Jan 16.
Approximately 50% of prostate cancer (PCa) patients in Western countries harbor ERG rearrangement with concurrent ERG overexpression. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations was unclear.
Fluorescence in situ hybridization and immunohistochemistry were utilized to detect ERG rearrangement and SOX4 expression. Cellular function was evaluated by transwell, wound healing assays, and cell adhesion assay, respectively. Interaction between ERG and SOX4 was arrayed by co-immunoprecipitation, Real-time PCR, Western blot, and siRNA. Direct binding of ERG to the promoter of SOX4, as well as epigenetic modifications of their promoters after TGF-β1 treatment was monitored by chromatin immunoprecipitation.
ERG regulated SOX4 expression via binding to its promoter. Silencing both of them showed duplicate effects on restoring the epithelial characteristics, increasing cellular adhesion and decreasing capacity of cellular migration and invasion. ERG and SOX4 have cooperative roles in TGF-β1-induced epithelial to mesenchymal transition (EMT) process. In addition, TGF-β1 stimulation increased levels of chromatin marks associated with active genes (H3K4me3, H416ac), and decreased levels of repressive marks (H3K27me3) at their promoters. 5-aza and TSA treatment changed expressions of ERG and SOX4. Clinically, overexpression of SOX4 is associated with ERG rearrangement status in PCa and ERG+/SOX4+ defined a subset of PCa patients with poor prognosis.
Our findings define a key role for ERG/SOX4 in the development of a subset of PCa and highlight the clinical importance of identifying molecularly defined tumor subgroups.
在西方国家，约有 50%的前列腺癌（PCa）患者存在 ERG 重排并伴有 ERG 过表达。SOX4 的过表达已被证明在包括 PCa 在内的多种癌症中发挥重要作用。然而，这两种关键遗传异常之间的联系尚不清楚。
利用荧光原位杂交和免疫组织化学检测 ERG 重排和 SOX4 表达。通过 Transwell、划痕愈合实验和细胞黏附实验分别评估细胞功能。通过共免疫沉淀、实时 PCR、Western blot 和 siRNA 排列 ERG 和 SOX4 之间的相互作用。通过染色质免疫沉淀监测 ERG 与 SOX4 启动子的直接结合以及 TGF-β1 处理后它们启动子的表观遗传修饰。
ERG 通过结合其启动子调节 SOX4 的表达。沉默两者都能起到双重作用，恢复上皮特征，增加细胞黏附，降低细胞迁移和侵袭能力。ERG 和 SOX4 在 TGF-β1 诱导的上皮间质转化（EMT）过程中具有协同作用。此外，TGF-β1 刺激增加了与其启动子相关的活跃基因的染色质标记物（H3K4me3、H416ac）水平，并降低了其抑制性标记物（H3K27me3）水平。5-aza 和 TSA 处理改变了 ERG 和 SOX4 的表达。临床上，SOX4 的过表达与 PCa 中的 ERG 重排状态相关，并且 ERG+/SOX4+定义了一组预后不良的 PCa 患者。
我们的研究结果定义了 ERG/SOX4 在亚组 PCa 发展中的关键作用，并强调了确定分子定义的肿瘤亚组的临床重要性。
