title: Miz1, a Novel Target of ING4, Can Drive Prostate Luminal Epithelial Cell Differentiation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Miz1 is a newly identified ING4-induced target gene which can drive prostate luminal epithelial cell differentiation although it is not absolutely required. Prostate 77:49-59, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Berger
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Miranti
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D051741:Kruppel-Like Transcription Factors; D025521:Tumor Suppressor Proteins; C107961:ZBTB17 protein, human
keywords: Myc; RNA-Seq; chromatin; human; integrins