NFIB regulates transcriptional networks that control the development of prostatic hyperplasia

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

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

A functional complex consisting of androgen receptor (AR) and forkhead boxA1 (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 NFIBb in dingsites 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 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, 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.

Original languageEnglish (US)
Pages (from-to)1094-1109
Number of pages16
JournalEndocrinology
Volume157
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Endocrinology

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    Grabowska, M. M., Kelly, S. M., Reese, A. L., Cates, J. M., Case, T. C., Zhang, J., Degraff, D. J., Strand, D. W., Miller, N. L., Clark, P. E., Hayward, S. W., Gronostajski, R. M., Anderson, P. D., & Matusik, R. J. (2016). NFIB regulates transcriptional networks that control the development of prostatic hyperplasia. Endocrinology, 157(3), 1094-1109. https://doi.org/10.1210/en.2015-1312