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Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition

Oncogene volume 29, pages 576–588 (2010)Cite this article

Abstract

Reexpression of hypermethylated tumor suppressor genes using DNA methyltransferase (DNMT) and histone deacetylase inhibitors occurs by a mechanism whereby promoter demethylation is the dominant event. In support of this model, we found in acute myeloid leukemia cells with hypermethylated p15INK4B and E-cadherin promoters that the DNMT inhibitor, 5-aza-2′-deoxycytidine, induced p15INK4B and E-cadherin expression, and decreased levels of DNA methylation, histone H3 lysine 9 (H3K9) methylation and SUV39H1 associated with p15INK4B and E-cadherin promoters. On the basis of these observations, we examined whether promoter demethylation was dominant to H3K9 demethylation in p15INK4B and E-cadherin reexpression. We observed that SUV39H1 short hairpin RNA and chaetocin, a SUV39H1 inhibitor, induced p15INK4B and E-cadherin expression and H3K9 demethylation without promoter demethylation. Reexpression of hypermethylated p15INK4B and E-cadherin required histone H3K9 demethylation that was achieved directly by inhibiting SUV39H1 expression or activity, or indirectly by decreasing the amount of SUV39H1 associated with the p15INK4B and E-cadherin promoters using 5-aza-2′-deoxycytidine. The results from this study highlight the potential of H3K9 methyltransferases as therapeutic targets for reactivating expression of hypermethylated genes.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research, Canada Foundation for Innovation, and the Saskatchewan Health Research Foundation. CRG is a CIHR-RPP New Investigator. AL is a Rethink Breast Cancer PDF.

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  1. S A Scott

    Present address: 4Current address: Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA,

Authors and Affiliations

  1. Cancer Stem Cell Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    A Lakshmikuttyamma, S A Scott, J F DeCoteau & C R Geyer

  2. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    A Lakshmikuttyamma, S A Scott & J F DeCoteau

  3. Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    C R Geyer

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Lakshmikuttyamma, A., Scott, S., DeCoteau, J. et al. Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition. Oncogene 29, 576–588 (2010). https://doi.org/10.1038/onc.2009.361

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