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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Jin Gu Cho1,2, Seho Park3, Chae Hyun Lim4, Hong Sook Kim2, Seung Yong Song5, Tae-Young Roh4, Jong-Hyuk Sung6, Wonhee Suh7, Seok-Jin Ham4, Key-Hwan Lim2, Sang Gyu Park2
1Department of Biomedical Science, CHA University, Sungnam-si, Gyunggi-do, Korea
2Laboratory for Tracing of Gene Function, Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Gyunggi-do, Korea
3Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
4Division of Integrative Biosciences & Biotechnology, Pohang University of Science & Technology (POSTECH), Pohang, Gyeongbuk, Korea
5Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, Korea
6Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea
7Department of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul, Korea
Sang Gyu Park, e-mail: [email protected]
Keywords: ZNF224, miR-663a, p53, p21, apoptosis
Received: December 22, 2015 Accepted: March 31, 2016 Published: April 20, 2016
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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