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Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells

Oncogene volume 27, pages 1376–1386 (2008)Cite this article

Abstract

Dysregulation of DNA methyltransferase (DNMT)1 expression is associated with cellular transformation, and inhibition of DNMT1 exerts antitumorigenic effects. Here, we report that DNMT1 abnormally expressed in HeLa cells is downregulated by a histone deacetylase (HDAC) inhibitor apicidin, which is correlated with induction of repressive histone modifications on the promoter site. Apicidin selectively represses the expression of DNMT1 among DNMTs in HeLa cells, independent of cell cycle arrest at G0/G1. Furthermore, apicidin causes a significant reduction in the recruitment of RNA polymerase II into the promoter. Chromatin immunoprecipitation analysis shows that even though apicidin causes global hyperacetylation of histone H3 and H4, localized deacetylation of histone H3 and H4 occurs at the E2F binding site, which is accompanied by the recruitment of pRB and the replacement of P/CAF with HDAC1 into the sites. In addition, K4-trimethylated H3 on nucleosomes associated with the transcriptional start site is depleted following apicidin treatment, whereas repressive markers, K9- and K27-trimethylation of H3 are enriched on the site. The downregulation of DNMT1 expression seems to require de novo protein synthesis, because the apicidin effect is antagonized by cycloheximide treatment. Moreover, knock down of DNMT1 with siRNA induces the apoptosis of HeLa cells, indicating that downregulation of DNMT1 might be a good strategy for therapeutics of human cervix cancer. Collectively, our findings will provide a mechanistic rationale for the use of HDAC inhibitors in cancer therapeutics.

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Abbreviations

ChIP:

chromatin immunoprecipitation

DNMT:

DNA methyltransferase

HAT:

histone acetyltransferase

HDAC:

histone deacetylase

Pol II:

RNA polymerase II

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Acknowledgements

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (R01-2006-000-10707-0).

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  1. J S You and J K Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

    J S You, J K Kang, E K Lee, J C Lee, S H Lee, Y J Jeon, D H Koh, E-J Cho & J-W Han

  2. Division of Molecular and Life Sciences, Hanyang University, Ansan, Republic of Korea

    S H Ahn

  3. Department of Molecular Bioscience, Kangwon National University, Chuncheon, Republic of Korea

    D-W Seo

  4. Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Republic of Korea

    H Y Lee

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You, J., Kang, J., Lee, E. et al. Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells. Oncogene 27, 1376–1386 (2008). https://doi.org/10.1038/sj.onc.1210776

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