Title: Poster Communications from the 6th International Symposium on Hormonal Oncogenesis
Abstract: The homeodomain transcription factor Nkx3.1 is an androgen-regulated protein that plays important roles in prostate development and carcinogenesis.In humans and mice, reductions in Nkx3.1 protein levels are associated with prostate tumor initiation.The primary growth defect in Nkx3.1 mutant mice is a delayed exit from the cell cycle by differentiating luminal epithelial cells, leading to epithelial hyperplasia and PIN.Recent studies have identified Nkx3.1 as a marker for a luminal epithelial castration-resistant stem cell that can function as a cell of origin for prostate cancer.A complete understanding of how Nkx3.1 functions in prostate development, stem cell renewal and tumorigenesis can only be gained by ascertaining its target genes.Here, we have used chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) to identify Nkx3.1 binding sites in the genomes of a human prostate cancer cell line (LNCaP) as well as the normal mouse prostate.We obtained 7 to 15 million uniquely mapped tags each from Nkx3.1 ChIP-seq using LNCaP cells or Nkx3.1+/+,Nkx3.1+/-andNkx3.1-/-mouse prostates.This led to the identification of about 8,000 Nkx3.1 binding sites in the genome (the Nkx3.1 cistrome).The binding site data were integrated with gene expression profiling results from Nkx3.1 mutant mice to yield a core set of "direct" Nkx3.1 target genes.Several transcription factor-binding motifs including the Nkx3.1 consensus motif were highly enriched in the Nkx3.1-boundfragments.These studies of a key prostate developmental regulator should shed light on the process of prostate tumorigenesis.[