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Genome-Wide Promoter Analysis of the SOX4 Transcriptional Network in Prostate Cancer Cells

¹ Program in Genetics and Molecular Biology, ² Department of Pathology and Laboratory Medicine, and ³ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; ⁴ Division of Genetics, Department of Medicine and ⁵ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School; ⁶ Harvard/MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts; and ⁷ Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, Massachusetts

Requests for reprints: Carlos S. Moreno, Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University, Whitehead Research Building, Room 105J, 615 Michael Street, Atlanta, GA 30322. Phone: 404-712-2809; Fax: 404-727-8538; E-mail: cmoreno{at}emory.edu.

Key Words: prostate cancer • SOX4 • transcription • systems biology • ChIP-chip

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 chromatin immunoprecipitation–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, namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 affects 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. [Cancer Res 2009;69(2):709–17]

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