title: 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.
authors.affiliation: Departments of Anti-Aging Medicine (K.T., T.U., S.I.) and Geriatric Medicine (K.T., T.U., S.I.) and Department of Urology (T.F., Y.H.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Pathology (T.S.), Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan; Genome Science Division (Sh.T., H.A.), Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan; Department of Urology (Sa.T.), Nihon University School of Medicine, Itabashi-ku, Tokyo 173-0032, Japan; and Division of Gene Regulation and Signal Transduction (S.I.), Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, 350-1241, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C496499:FOXA1 protein, human; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D051541:Hepatocyte Nuclear Factor 3-alpha; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012097:Repressor Proteins