The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer

Jian Wang, Abul Elahi, Abidemi Ajidahun, Whalen Clark, Jonathan Hernandez, Alex Achille, Ji Hui Hao, Edward Seto, David Shibata

    Research output: Contribution to journalArticle

    7 Scopus citations

    Abstract

    HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.

    Original languageEnglish (US)
    Pages (from-to)1198-1207
    Number of pages10
    JournalCancer Biology and Therapy
    Volume15
    Issue number9
    DOIs
    StatePublished - Sep 2014

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    Keywords

    • Colon cancer
    • Epigenetics
    • HPP1
    • Histone acetylase
    • Histone deacetylase inhibitors
    • Myc

    ASJC Scopus subject areas

    • Molecular Medicine
    • Oncology
    • Pharmacology
    • Cancer Research

    Cite this

    Wang, J., Elahi, A., Ajidahun, A., Clark, W., Hernandez, J., Achille, A., Hao, J. H., Seto, E., & Shibata, D. (2014). The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer. Cancer Biology and Therapy, 15(9), 1198-1207. https://doi.org/10.4161/cbt.29500