ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a.
ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a.
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DOI：
10.18632/oncotarget.8870
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Park SG
中科院分区：
文献类型：
--
作者：
Cho JG;Park S;Lim CH;Kim HS;Song SY;Roh TY;Sung JH;Suh W;Ham SJ;Lim KH;Park SG
ZNF 224是一种Krüppel相关的含盒锌指蛋白，通过与各种辅抑制因子相互作用来抑制基因转录。然而，其共有DNA序列和靶基因尚未完全确定。本研究通过ChIP测序鉴定了ZNF 224识别的5′-CAGC-3′的共有序列，并通过ELISA、SPR、qPCR和荧光素酶活性测定进一步证实了这一点。ZNF 224通过与miR-663 a启动子结合而增加miR-663 a的转录，miR-663 a启动子又与p53和p21的3′ UTR结合而降低其表达。miR-663 a拮抗剂可阻断ZNF 224对p21和p53的抑制作用，从而增强CPT诱导的细胞凋亡。使用人乳腺导管癌组织的分析显示，与非癌区域相比，ZNF 224和miR-663 a在癌中的表达增加。因此，ZNF 224通过miR-663 a作为转录激活因子降低p53和p21的表达，从而增加细胞存活并减少凋亡。综上所述，我们鉴定并表征了ZNF 224的DNA结合元件及其靶基因miR-663 a，这为ZNF 224通过miR-663 a下调乳腺癌中的p21和p53提供了新的见解。
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.
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