ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a

Abstract

// Jin Gu Cho 1, 2 , Seho Park 3 , Chae Hyun Lim 4 , Hong Sook Kim 2 , Seung Yong Song 5 , Tae-Young Roh 4 , Jong-Hyuk Sung 6 , Wonhee Suh 7 , Seok-Jin Ham 4 , Key-Hwan Lim 2 , Sang Gyu Park 2 1 Department of Biomedical Science, CHA University, Sungnam-si, Gyunggi-do, Korea 2 Laboratory for Tracing of Gene Function, Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Gyunggi-do, Korea 3 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 4 Division of Integrative Biosciences & Biotechnology, Pohang University of Science & Technology (POSTECH), Pohang, Gyeongbuk, Korea 5 Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, Korea 6 Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea 7 Department of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul, Korea Correspondence to: Sang Gyu Park, e-mail: sgpark@ajou.ac.kr Keywords: ZNF224, miR-663a, p53, p21, apoptosis Received: December 22, 2015      Accepted: March 31, 2016      Published: April 20, 2016 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.