Dataset Information

Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.

ABSTRACT: 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 TGFbeta, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis.

SUBMITTER: Scharer CD

PROVIDER: S-EPMC2629396 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.

Scharer Christopher D CD McCabe Colleen D CD Ali-Seyed Mohamed M Berger Michael F MF Bulyk Martha L ML Moreno Carlos S CS

Cancer research 20090101 2

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 ...[more]

PMID: 19147588

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Project description:Epigenetic changes, including aberrant DNA methylation, result in altered gene expression and play an important role in carcinogenesis. Phytochemicals such as sulforaphane (SFN) and 3,3'-diindolylmethane (DIM) are promising chemopreventive agents for the treatment of prostate cancer. Both have been shown to induce re-expression of genes, including tumor suppressor genes silenced in cancer cells, via modulation of epigenetic marks including DNA methylation. However, it remained unclear the effects SFN and DIM on DNA methylation at a genomic scale. The goal of this study was to determine the genome-wide effects of SFN and DIM on promoter methylation in normal prostate epithelial cells and prostate cancer cells. Both SFN and DIM treatment decreased DNA methyltransferase expression in normal prostate epithelial cells (PrEC), and androgen-dependent (LnCAP) and androgen-independent (PC3) prostate cancer cells. The effects of SFN and DIM on promoter methylation profiles in normal PrEC, LnCAP and PC3 prostate cancer cells were determined using methyl-DNA immunoprecipitation followed by genome-wide DNA methylation array. We showed widespread changes in promoter methylation patterns, including both increased and decreased methylation, in all three prostate cell lines in response to SFN or DIM treatments. In particular, SFN and DIM altered promoter methylation in distinct sets of genes in PrEC, LnCAP, and PC3 cells, but shared similar gene targets within a single cell line. We further showed that SFN and DIM reversed many of the cancer-associated methylation alterations, including aberrantly methylated genes that are dysregulated or are highly involved in cancer progression. Overall, our data suggested that both SFN and DIM are epigenetic modulators that have broad and complex effects on DNA methylation profiles in both normal and cancerous prostate epithelial cells. Results from our study may provide new insights into the epigenetic mechanisms by which SFN and DIM exert their cancer chemopreventive effects.

Project description:The transformation of prostate cancer from an androgen-dependent state to an androgen-independent state is a lethal progression. Alterations in transcriptional programs are the basis of prostate cancer deterioration. The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, mediates prostate cancer progression by functioning primarily through the ligand-activated transcription of target genes. Therefore, a detailed map of AR-regulated genes and AR genomic binding sites is required for hormone-naive and castration-resistant prostate cancer. Through the use of chromatin immunoprecipitation in combination with direct sequencing, 4,143 AR binding sites were defined in the LNCaP androgen-sensitive prostate cancer cell line. Using the same method, 2,380 AR binding regions were identified in the LNCaP-AI long-term androgen-deprived cell line. Approximately 8.5% (354/4,143) of the binding regions were mapped to within 2 kb of the transcription start site (TSS) in the LNCaP cells, while ?12.6% (299/2,380) were mapped to within 2 kb of the TSS in the LNCaP-AI cells. In total, the study mapped 2,796 genes in LNCaP cells and 1,854 genes in LNCaP-AI cells. The cell lines shared 789 mutual genes. In addition, gene ontology (GO) analysis of the genes revealed that there was a notable overlap between the GO terms in the LNCaP cells and LNCaP-AI cells. However, GO terms within the biological process domain that were only observed in the LNCaP-AI cells included the reproduction process, death, immune system process, multi-organism process, pigmentation and viral reproduction. The major genes in the different GO terms were TNFAIP8, RTN4, APP and SYNE1. Through analyzing the AR binding sites in the two cell types, the present study aimed to map potential AR-regulated genes, identify their associated transcription factors and provide a new perspective on the biological processes in the development of prostate cancer. The results provided a valuable data set that furthered the understanding of the genome-wide analysis of AR binding sites in prostate cancer cells, which may be exploited for the development of novel prostate cancer therapeutic strategies.

Dataset Information

Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.

Publications

Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.

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