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Miz1, a Novel Target of ING4, Can Drive Prostate Luminal Epithelial Cell Differentiation

Authors
  • Berger, Penny L.1
  • Winn, Mary E.2
  • Miranti, Cindy K.1
  • 1 laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, Michigan
  • 2 Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan
Type
Published Article
Journal
The Prostate
Publisher
Wiley (John Wiley & Sons)
Publication Date
Aug 16, 2016
Volume
77
Issue
1
Pages
49–59
Identifiers
DOI: 10.1002/pros.23249
PMID: 27527891
PMCID: PMC6739073
Source
PubMed Central
Keywords
License
Unknown

Abstract

BACKGROUND. How prostate epithelial cells differentiate and how dysregulation of this process contributes to prostate tumorigenesis remain unclear. We recently identified a Myc target and chromatin reader protein, ING4, as a necessary component of human prostate luminal epithelial cell differentiation, which is often lost in primary prostate tumors. Furthermore, loss of ING4 in the context of oncogenic mutations is required for prostate tumorigenesis. Identifying the gene targets of ING4 can provide insight into how its loss disrupts differentiation and leads to prostate cancer. METHODS. Using a combination of RNA-Seq, a best candidate approach, and chromatin immunoprecipitation (ChIP), we identified Miz1 as a new ING4 target. ING4 or Miz1 overexpression, shRNA knock-down, and a Myc-binding mutant were used in a human in vitro differentiation assay to assess the role of Miz1 in luminal cell differentiation. RESULTS. ING4 directly binds the Miz1 promoter and is required to induce Miz1 mRNA and protein expression during luminal cell differentiation. Miz1 mRNA was not induced in shING4 expressing cells or tumorigenic cells in which ING4 is not expressed. Miz1 dependency on ING4 was unique to differentiating luminal cells; Miz1 mRNA expression was not induced in basal cells. Although Miz1 is a direct target of ING4, and its overexpression can drive luminal cell differentiation, Miz1 was not required for differentiation. CONCLUSIONS. Miz1 is a newly identified ING4-induced target gene which can drive prostate luminal epithelial cell differentiation although it is not absolutely required.

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