Zinc finger transcription factor 191, directly binding to β-catenin promoter, promotes cell proliferation of hepatocellular carcinoma

Abstract

Activation of b-catenin, the central effector of the canonical wingless-type (Wnt) pathway, has been implicated in hepatocellular carcinoma (HCC). However, the transcription regulation mechanism of the b-catenin gene in HCC remains unknown. Here we report that human zinc finger protein 191 (ZNF191) is a potential regulator of b-catenin transcription. ZNF191, a Krüppel-like protein, specifically interacts with the TCAT motif, which constitutes the HUMTH01 microsatellite in the tyrosine hydroxylase (TH) gene ex vivo. We demonstrate that ZNF191 is significantly overexpressed in human HCC specimens and is associated with growth of human HCC cells. Global profiling of gene expression in ZNF191 knockdown human hepatic L02 cells revealed that the important Wnt signal pathway genes b-catenin and cyclin D1 messenger RNAs (mRNAs) are significantly downregulated. In agreement with transcription level, b-catenin and cyclin D1 proteins are also down-regulated in transient and stable ZNF191 knockdown L02 and hepatoma Hep3B cell lines. Moreover, significant correlation between ZNF191 and b-catenin mRNA expression was detected in human HCCs. Promoter luciferase assay indicated that ZNF191 can increase transcription activity of the full-length b-catenin (CTNNB1) promoter, and nucleotide (nt)-1407/-907 of the CTNNB1 promoter exhibited the maximum transcriptional activity. Electrophoretic mobility shift assay showed that purified ZNF191 protein can directly bind to the CTNNB1 promoter, and the binding region is located at nt-1254/-1224. Finally, we demonstrate that the key binding sequence of ZNF191 in vivo is ATTAATT. Conclusion: ZNF191 can directly bind to the CTNNB1 promoter and activate the expression of b-catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines. This study uncovers a new molecular mechanism of transcription regulation of the b-catenin gene in HCC.

Identification of a Functional Nuclear Localization Signal Mediating Nuclear Import of the Zinc Finger Transcription Factor ZNF24

“…Promoter luciferase assay indicated that the wild-type ZNF24 can increase transcription activity of CTNNB1 promoter by about 2.7 fold compared with transfecting control vector (Figure 7). This is consistent with previous reports that ZNF24 can activate β-Catenin in hepatocellular carcinoma cell lines[9]. In contrast, when the ZF region was missing, the ZNF24 mutants failed to activate the CTNNB1 promoter (Figure 7, compare dZF1-2 or p1-250 with WT).…”

“…Allelic variations of HUMTH01 are known to have a quantitative silencing effect on TH gene expression and to correlate with quantitative and qualitative changes in the binding by ZNF24[8]. ZNF24 also can directly bind to CTNNB1 promoter, and activates the expression of β-Catenin and promotes cell proliferation of hepatocellular carcinoma[9]. ZNF24 shows 94% identity to its mouse homologue Zfp191, which is the most highly conserved among the human-mouse SCAN family member orthologues pairs[10].…”

Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer

“…In fact, only a few previous studies have provided evidence for a transcriptional mechanism of β -catenin regulation. 24, 25 Here our study provides solid evidence for a transcriptional mechanism of β -catenin regulation in CRC carcinogenesis. The ChIP, EMSA and luciferase assays revealed that Elf3 could bind to the promoter of β -catenin and transactivate its transcription.…”

Comorbidities Among Persons With Incident Psychiatric Condition

“…ZNF 191 may activate the expression of β-catenin and its downstream target genes (Liu et al, 2012). β-catenin has been implicated in depression (Dias et al, 2014), glucose metabolism (Elghazi et al, 2012), and idiopathic pulmonary fibrosis (Chilosi et al, 2003).…”