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Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells

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Abstract

Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD+ dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer.

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Acknowledgments

This work was funded in part by NIH grant CA88843 and the Breast Cancer Research Foundation.

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Yi Huang, Shauna N. Vasilatos, Lamia Boric, Patrick G. Shaw & Nancy E. Davidson

  2. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Yi Huang & Nancy E. Davidson

  3. Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    Patrick G. Shaw

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  1. Yi Huang
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  2. Shauna N. Vasilatos
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  3. Lamia Boric
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Correspondence to Yi Huang.

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Huang, Y., Vasilatos, S.N., Boric, L. et al. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat 131, 777–789 (2012). https://doi.org/10.1007/s10549-011-1480-8

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  • DOI: https://doi.org/10.1007/s10549-011-1480-8

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