title: Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia.
abstract: A functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia.
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Grabowska
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kelly
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Reese
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Case
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: David J
authors.initials: DJ
authors.lastname: DeGraff
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Strand
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Miller
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gronostajski
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Anderson
authors.affiliation: Department of Urologic Surgery (M.M.G., T.C.C., J.Z., N.L.M., P.E.C., S.W.H., R.J.M.), Department of Pathology, Microbiology, and Immunology (J.M.C.), and Vanderbilt-Ingram Cancer Center (P.E.C., R.J.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biological Sciences (S.M.K., A.L.R., P.D.A.), Salisbury University, Salisbury, Maryland 21801; Department of Pathology (D.J.G.), Penn State University College of Medicine, Hershey, Pennsylvania 17033; Department of Urology (D.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Cancer Biology (S.W.H.), NorthShore HealthSystem Research Institute, Evanston, Illinois 60201; Department of Biochemistry, Genetics, Genomics and Bioinformatics Program (R.M.G.), University at Buffalo, Buffalo, New York 14203; and Department of Cell and Developmental Biology (R.J.M.), Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000235:genetics*; D011467:Prostate; D011470:Prostatic Hyperplasia / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D051839:NFI Transcription Factors; C484683:Nfib protein, mouse; D011944:Receptors, Androgen