Integrative analysis of FOXP1 function reveals a tumor-suppressive effect in prostate cancer.

Abstract

The transcriptional network of the androgen receptor (AR), a key molecule of prostate cancer, is frequently modulated by interactions with other transcriptional factors such as forkhead box protein A1 (FOXA1). However, global regulatory mechanisms of AR signaling mediated by such factors have not been well investigated. Here we conducted a chromatin immunoprecipitation sequence analysis, which revealed that another FOX family, FOXP1, is specifically regulated by both AR and FOXA1. We also found that FOXP1 acts as a tumor suppressor in prostate cancer through inhibiting cell proliferation and migration. We generated an extensive global map of FOXP1 binding sites and found that FOXP1 is directly involved in AR-mediated transcription. We demonstrated that FOXP1 has a repressive effect on AR-induced transcriptional activity or histone modification in enhancer regions. Moreover, by a global analysis of androgen-mediated transcriptional networks, we observed enrichment of FOXP1 binding genes in the gene cluster negatively regulated by FOXP1. Evaluation of FOXP1 expression in clinical samples indicated that the decreased expression of FOXP1 is another prognostic factor of prostate cancer. Taken together, our results suggest a novel mechanism in which AR-induced FOXP1 functions as a direct modulator of the AR and FOXA1 centric global transcriptional network.