Abstract
ZBP-89 (Zfp148, ZNF148) is a Kruppel-type zinc-finger family transcription factor that binds to GC-rich DNA elements. Earlier studies in cell lines demonstrated that ZBP-89 cooperates with Wnt β-catenin signaling by inducing β-catenin gene expression. Since β-catenin levels are normally highest at the crypt base, we examined whether ZBP-89 is required for stem cell maintenance. Lineage-tracing using a Zfp148CreERT2 transgenic line demonstrated expression in both intestine and colonic stem cells. Deleting the Zfp148 locus in the colon using the Cdx2NLSCreERT2 transgene, reduced the size and number of polyps formed in the Apc-deleted mice. Since colon polyps form in the presence of butyrate, a short chain fatty acid that suppresses cell growth, we examined the direct effect of butyrate on colon organoid survival. Butyrate induced senescence of colon organoids carrying the Apc deletion, only when Zfp148 was deleted. Using quantitative PCR and chromatin immunoprecipitation, we determined that butyrate treatment of colon cell lines suppressed ZNF148 gene expression, inducing CDKN2a (p16Ink4a) gene expression. Collectively, Zfp148 mRNA is expressed in CBCs, and is required for stem cell maintenance and colonic transformation. Butyrate induces colonic cell senescence in part through suppression of ZBP-89 gene expression and its subsequent occupancy of the CDKN2A promoter.
Highlights
Zinc Finger Binding Protein-89 kDa (ZBP-89, human ZNF148 or mouse Zfp148 loci) is a ubiquitously expressed Krüppel-type zinc finger transcription factor that binds GC-rich DNA elements [1, 2]
We previously showed that histone deacetylase inhibition (HDACi), e.g., with butyrate or trichostatin A (TSA) contributes to ZBP-89 induction of CDKN1B (p21Waf1) and its proteinprotein interaction with tumor suppressor proteins p53, ataxia telangiectasia mutated (ATM), and p300, a histone acetyltransferase (HAT) [2,3,4]
To localize Zfp148 mRNA, we performed in situ hybridization (ISH) in the small intestine and found that the highest level of mRNA expression occurred at the crypt base (Figure 1C)
Summary
Zinc Finger Binding Protein-89 kDa (ZBP-89, human ZNF148 or mouse Zfp148 loci) is a ubiquitously expressed Krüppel-type zinc finger transcription factor that binds GC-rich DNA elements [1, 2]. Having established that ZBP-89 and β-catenin cooperate in normal colonic mucosal restitution, we tested and found that ZBP89 contributes to intestinal polyp formation initiated by deletion of the Apc locus [9]. Conditional deletion of the Zfp148 locus in intestinal epithelial cells reduced the expected number of small intestinal polyps in a mouse model of deleted Apc, demonstrating that ZBP-89 is required for β-catenindependent polyp formation [9]. We found that β-catenin www.impactjournals.com/oncotarget binds to the ZNF148 promoter stimulating ZBP-89 gene expression. ZBP-89 protein binds to the CTNNB1 (β-catenin) promoter inducing β-catenin transcription. In this way, ZBP-89 contributes to a feedforward gene expression loop that can maintain elevated levels of β-catenin when and where Wnt signaling is high [9], such as in the normal stem cell niche and in colon cancer. We showed that ZBP-89 expression correlates with poor survival after surgical resection for colorectal cancer and that ZBP-89 protein expression is elevated in colorectal cancer (CRC) [9]
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