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Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation

Oncogene volume 22, pages 8902–8911 (2003)Cite this article

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the fifth most frequent cancer in the US. Several genetic and epigenetic alterations are associated with HNSCC tumorigenesis, including inactivation of CDKN2A, which encodes the p16 tumor suppressor, in cell lines and primary tumors by DNA methylation. Reactivation of tumor suppressor genes by DNA-demethylating agents and histone deacetylase (HDAC) inhibitors shows therapeutic promise for other cancers. Therefore, we investigated the ability of these agents to reactivate p16 in Tu159 HNSCC cells. Treatment of cells with 5-aza-2′deoxycytidine (5-aza-dC) increases CDKN2A expression and slightly increases histone H3 acetylation at this gene. No reactivation of CDKN2A is observed upon treatment with the HDAC inhibitor trichostatin A (TSA), but synergistic reactivation of CDKN2A is observed upon sequential treatment of Tu159 cells with both 5-aza-dC and TSA. Silencing of CDKN2A in Tu159 cells is correlated with increased methylation of histone H3 at lysine 9 and decreased methylation at lysine 4 relative to the upstream p15 gene promoter. Interestingly, global levels of H3-K9 methylation are decreased upon treatment with 5-aza-dC. Together these data indicate that DNA methylation is a dominant epigenetic mark for silencing of CDKN2A in Tu159 tumor cells. Moreover, changes in DNA methylation can reset the histone code by impacting multiple H3 modifications.

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Acknowledgements

We thank Paula Holton for assisting with tissue culture of Tu159, Bobby Brown for assistance in culturing HeLa cells, and Diane Edmondson for technical advice on immunoblotting. We thank Joie Haviland for sharing unpublished information regarding the methylation status of RARβ, DAPK, and E-cadherin in Tu159 cells. This work was supported by grants from the USAMRC Breast Cancer Research Program and the Texas Higher Education Board Advanced Research Program to SYRD.

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  1. James R Bone

    Present address: Research and Development, Upstate Biotechnology, Charlottesville, VA, 22903, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, MD Anderson Cancer Center, University of Texas, Houston, 77030, TX, USA

    Madelene M Coombes, James R Bone & Sharon YR Dent

  2. Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, 77030, TX, USA

    Katrina L Briggs & Gary L Clayman

  3. Department of Pathology, MD Anderson Cancer Center, University of Texas, Houston, 77030, TX, USA

    Adel K El-Naggar

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  1. Madelene M Coombes
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Correspondence to Sharon YR Dent.

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Coombes, M., Briggs, K., Bone, J. et al. Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation. Oncogene 22, 8902–8911 (2003). https://doi.org/10.1038/sj.onc.1207050

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