Nfib regulates transcriptional networks that control the development of prostatic hyperplasia

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 (ChIP-Seq) 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 following dihydrotestosterone (DHT) treatment of LNCaP cells, while NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and super-induction 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 (BPH), 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 co-regulator of AR action in the prostate and in controlling prostatic hyperplasia.

Endocrinology. 2015 Dec 17 [Epub ahead of print]

Magdalena M Grabowska, Stephen M Kelly, Amy L Reese, Justin M Cates, Tom C Case, Jianghong Zhang, David J DeGraff, Douglas W Strand, Nicole L Miller, Peter E Clark, Simon W Hayward, Richard M Gronostajski, Philip D Anderson, Robert J Matusik

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Biological Sciences, Salisbury University, Salisbury MD. , Department of Biological Sciences, Salisbury University, Salisbury MD. , Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Pathology, PA State University College of Medicine, Hershey PA. , Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN. , Department of Biochemistry, Genetics, Genomics & Bioinformatics Program, University at Buffalo, Buffalo NY. , Department of Biological Sciences, Salisbury University, Salisbury MD. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN.

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