Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia.

Grabowska MM, Kelly SM, Reese AL, Cates JM, Case TC, Zhang J, DeGraff DJ, Strand DW, Miller NL, Clark PE, Hayward SW, Gronostajski RM, Anderson PD, Matusik RJ
Endocrinology. 2016 157 (3): 1094-109

PMID: 26677878 · PMCID: PMC4769366 · DOI:10.1210/en.2015-1312

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.

MeSH Terms (22)

Animals Cell Line, Tumor Cell Proliferation Chromatin Immunoprecipitation Fluorescent Antibody Technique Gene Expression Regulation Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Gene Regulatory Networks Hepatocyte Nuclear Factor 3-alpha Humans Immunohistochemistry Male Mice Mice, Knockout NFI Transcription Factors Prostate Prostatic Hyperplasia Prostatic Neoplasms Receptors, Androgen Sequence Analysis, DNA Sequence Analysis, RNA

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