Abstract
ICBP90, inverted CCAAT box-binding protein of 90 kDa, has been reported as a regulator of topoisomerase IIα expression. We present evidence here that ICBP90 binds to methyl-CpG when at least one symmetrically methylated-CpG dinucleotides is presented as its recognition sequence. A SET and RING finger-associated (SRA) domain accounts for the high binding affinity of ICBP90 for methyl-CpG dinucleotides. This protein constitutes a complex with HDAC1 also via its SRA domain, and bound to methylated promoter regions of various tumor suppressor genes, including p16INK4Aand p14ARF, in cancer cells. It has been reported that expression of ICBP90 was upregulated by E2F-1, and we confirmed that the upregulation was caused by binding of E2F-1 to the intron1 of ICBP90, which contains two E2F-1-binding motifs. Our data also revealed accumulation of ICBP90 in breast-cancer cells, where it might suppress expression of tumor suppressor genes through deacetylation of histones after recruitment of HDAC1. The data reported here suggest that ICBP90 is involved in cell proliferation by way of methylation-mediated regulation of certain genes.
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Acknowledgements
We thank Y Miki, F Kasumi, and M Yoshimoto at The Japanese Foundation of Cancer Research (Tokyo, Japan) for offering breast cancer samples, S Ishii (RIKEN, Tsukuba, Japan) for obtaining HDAC1-FLAG expression plasmid, M Nishida (Kasumigaura National Hospital, Tsuchiura, Japan) for obtaining Ishikawa3-H-12 cells, and all our colleagues, in particular, T Katagiri and A Konuma for analysis of breast cancer samples, and T Shimokawa for constructing psiU6BX3 vector. This work was supported in part by Research for the Future Program Grant #00L01402 from the Japan Society for the Promotion of Science.
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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).
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Unoki, M., Nishidate, T. & Nakamura, Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23, 7601–7610 (2004). https://doi.org/10.1038/sj.onc.1208053
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DOI: https://doi.org/10.1038/sj.onc.1208053
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