Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.
Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-08-3415
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Moreno, Carlos S.
中科院分区：
文献类型：
--
作者：
Scharer, Christopher D.;McCabe, Colleen D.;Ali-Seyed, Mohamed;Berger, Michael F.;Bulyk, Martha L.;Moreno, Carlos S.
SOX4是脊椎动物重要的发育转录因子，是多种组织精确分化和增殖所必需的。此外，SOX4在许多人类恶性肿瘤中过表达，但SOX4在癌症进展中的确切作用尚不清楚。在这里，我们已经确定了SOX4的直接转录靶点，使用全基因组定位ChIP-chip分析和短暂过表达，然后在前列腺癌模型细胞系中进行表达谱分析。我们还使用蛋白质结合微阵列获得了一种新的SOX4特异性位置-权重矩阵，并确定SOX4结合位点富集于SOX4结合的启动子区域。SOX4的直接转录靶点包括EGFR、HSP70、Tenascin C、frizzled5、Patched-1和δ -样1等几种关键的细胞调节因子。我们还发现SOX4可靶向MLL、FOXA1、ZNF281和NKX3-1等23种转录因子。此外，SOX4还可直接调控rna诱导沉默复合体（RISC）的三种组分的表达，即Dicer、Argonaute 1、这些数据为SOX4如何影响发育信号通路以及这些变化如何通过调控涉及microRNA加工、转录调控、TGFβ、Wnt、Hedgehog和Notch通路、生长因子信号通路和肿瘤转移的基因网络影响癌症进展提供了新的见解。
SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the exact role of SOX4 in cancer progression is not well understood. Here we have identified the direct transcriptional targets of SOX4 using a combination of genome-wide localization ChIP-chip analysis and transient overexpression followed by expression profiling in a prostate cancer model cell line. We have also used protein-binding microarrays to derive a novel SOX4-specific position-weight matrix and determined that SOX4 binding sites are enriched in SOX4-bound promoter regions. Direct transcriptional targets of SOX4 include several key cellular regulators such as EGFR, HSP70, Tenascin C, Frizzled-5, Patched-1, and Delta-like 1 We also show that SOX4 targets 23 transcription factors such as MLL, FOXA1, ZNF281, and NKX3-1 In addition, SOX4 directly regulates expression of three components of the RNA-induced silencing complex (RISC), namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 impacts developmental signaling pathways and how these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, the TGFβ, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis.