Systems analysis of the prostate tumor suppressor NKX3.1 substantiates roles in DNA repair and a transcriptional program that drives luminal cell differentiation

ABSTRACT: NKX3.1 is an androgen-regulated, prostate-specific gene located on chromosome 8p21, a region frequently undergoing allelic loss in human prostate cancer. Mice deficient in NKX3.1 show signs of epithelial de-differentiation and develop dysplasia and prostatic intraepithelial neoplasia (PIN) that progresses to overt prostate cancer when combined with deletions of additional tumor suppressors such as PTEN or p27Kip1. Although NKX3.1 displays the typical features of an NK class homeobox transcription factor, mechanisms of NKX3.1-mediated tumor suppression remain insufficiently understood because neither the transcriptional program governed by NKX3.1 nor its interacting proteins have been comprehensively revealed. Adenoviruses were created that constitutively express either GFP alone, or GFP and NKX3.1 (Ad-GFP and Ad-GFP-NKX3.1 viruses, respectively). PrEC LH cells were infected with these viruses and were harvested at 7h and 10h after infection. Using affinity purification and tandem mass spectrometry, we have established an extensive NKX3.1 interactome. In particular, we found that the transcription factor forms stable complexes with the DNA repair proteins Ku70, Ku80, and PARP, interactions that provide a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of immortalized human prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human PIN devoid of NKX3.1. Pathway and network analyses suggested that NKX3.1 actuates a fundamental cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-Myc and interferon-STAT signaling and activation of tumor suppressor pathways.

ORGANISM(S): Homo sapiens

SUBMITTER: Roy Williams 

PROVIDER: E-GEOD-47030 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress