Abstract
ZNF224 is a Krüppel-associated box-containing zinc-finger protein which represses gene transcription by interacting with various co-repressors. However, its consensus DNA sequences and target genes are not fully identified. In this study, we identified and characterized consensus DNA sequences containing 5′-CAGC-3′; recognized by ZNF224 through ChIP-sequencing, which further confirmed by ELISA, SPR, qPCR, and luciferase activity assay. ZNF224 increased miR-663a transcription by binding to miR-663a promoter, which in turn binds to 3′; UTR of p53 and p21 to decrease their expression. miR-663a antagonist abolished ZNF224-mediated suppression of p21 and p53, resulting in the enhanced apoptosis by CPT. The analyses using human breast ductal carcinoma tissues exhibited that the expression of ZNF224 and miR-663a was increased in cancer compared to non-cancer region. Consequently, ZNF224 increases cell survival and decreases apoptosis by decreasing the expression of p53 and p21 via miR-663a as a transcriptional activator. Taken together, we identified and characterized DNA binding element of ZNF224, and its target genes, miR-663a, which provides a novel insight in the down-regulation of p21 and p53 via miR-663a by ZNF224 in breast cancer.
Highlights
Transcription factor (TF) represses or activates transcription of target genes by binding to its DNA binding elements during a variety of cellular processes
Apoptosis analysis using FACS showed that subG1 population induced by CTP in ZNF224 over-expression cell line was lower than E.V control (Figure 2C), whereas subG1 population of ZNF224 knock-down cell line was higher than control shRNA (Figure 2D)
ZNF224, one of KRAB-ZFPs, has been known as a transcriptional repressor of aldolase A, mitochondrial citrate carrier, and A20 [10, 14, 17,18], ZNF224 acts as co-activator of WT1 to increase the gene expression, including Bax, Bak, Vitamin D receptor (VDR), bag3, and A1/Bfl1 [33]
Summary
Transcription factor (TF) represses or activates transcription of target genes by binding to its DNA binding elements during a variety of cellular processes. Krüppellike associated box-zinc finger proteins (KRAB-ZFPs), is a member of DNA binding protein family [1]. KRAB-ZFPs have one or more KRAB A boxes, and/. A KRAB B box, or a SCAN-domain, a leucine-rich region that is found in a small subset of KRAB-ZFPs [34]. It has been known that KRAB domain of ZFP binds to corepressor proteins and/or TFs via proteinprotein interactions, resulting in transcriptional repression of target genes [5,6]. KRAB-ZFPs forms complex with KRAB-associated protein 1 (KAP1), one of corepressor as well as a mediator of chromatin remodeling complex, binds to its corresponding DNA consensus sequence to silence gene expression [7,8,9]
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