Identification of the Transformational Properties and Transcriptional Targets of the Oncogenic SRY Transcription Factor SOX4

摘要

SOX4 is a critical developmental transcription factor in vertebrates and is required for precise proliferation and differentiation in multiple tissues. SOX4 has also been implicated in tumorigenesis of multiple tumor types and has been shown by our lab to be upregulated in prostate cancer. However, the exact molecular role and the genes SOX4 transcriptionally influences remain unknown. Using chromatin immunoprecipitation coupled to DNA microarrays (ChIP- chip) we have identified 282 high confidence SOX4 target genes and 3600 genomic binding sites. We have also used a unique protein binding, double-stranded DNA microarray to determine a novel SOX4 position-weight matrix for in silico binding site searches. Direct targets of SOX4 include key cellular regulators such as EGFR, Tenascin C, Frizzled-5 and Patched-1. In addition, SOX4 impacts other transcriptional networks through regulation of 23 transcription factors. We also show that SOX4 impacts the microRNAprocessing pathway through direct regulation of Dicer and Argonaute 1. For the first time, these data provide a snapshot of the global transcriptional regulatory network of SOX4 in prostate cancer. In tandem to molecular studies of SOX4 we have developed mice that harbor a prostate specific deletion of SOX4. Initial studies of our first mouse suggest that loss of SOX4 in the prostate has detrimental effects on fertility. While preliminary, these findings are exciting and hit at a previously unknown biological role for SOX4.