title: Transcription Factor ZBP-89 Drives a Feedforward Loop of β-Catenin Expression in Colorectal Cancer.
abstract: In colorectal cancer, APC-mediated induction of unregulated cell growth involves posttranslational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10% of colorectal tumors also exhibit increased CTNNB1 mRNA. Here, we show in colorectal cancer that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of colorectal cancer. Conditional deletion of Zfp148 in a mouse model of Apc-mediated intestinal polyps demonstrated that ZBP-89 was required for polyp formation due to induction of Ctnnb1 gene expression. Chromatin immunoprecipitation (ChIP) and EMSA identified a ZBP-89-binding site in the proximal promoter of CTNNB1 Reciprocally, siRNA-mediated reduction of CTNNB1 expression also decreased ZBP-89 protein. ChIP identified TCF DNA binding sites in the ZNF148 promoter through which Wnt signaling regulates ZNF148 gene expression. Suppression of either ZNF148 or CTNNB1 reduced colony formation in WNT-dependent, but not WNT-independent cell lines. Therefore, the increase in intracellular β-catenin protein initiated by APC mutations is sustained by ZBP-89-mediated feedforward induction of CTNNB1 mRNA. Cancer Res; 76(23); 6877-87. ©2016 AACR.
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Essien
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sinju
authors.initials: S
authors.lastname: Sundaresan
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ramon
authors.initials: R
authors.lastname: Ocadiz-Ruiz
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chavis
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Tsao
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Tessier
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hayes
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Amanda
authors.initials: A
authors.lastname: Photenhauer
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Milena
authors.initials: M
authors.lastname: Saqui-Salces
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan. merchanj@umich.edu.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Juanita L
authors.initials: JL
authors.lastname: Merchant
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; C491741:Zfp148 protein, mouse; D051176:beta Catenin