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Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs

Oncogene volume 24, pages 8061–8075 (2005)Cite this article

Abstract

The mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene following chemotherapy can severely limit the efficacy of anticancer agents; however, the manner by which cells acquire high levels of Pgp has not been defined. Herein, we demonstrate that chemotherapeutic drugs induce specific epigenetic modifications at the MDR1 locus, concomitant with MDR1 upregulation mediated by transcriptional activation and a potential post-transcriptional component. We have established that the mechanisms are not mutually exclusive and are dependent on the methylation state of the MDR1 promoter. MDR1 upregulation did not result in further changes to the CpG methylation profile. However, dramatic changes in the temporal and spatial patterning of histone modifications occurred within the 5′ hypomethylated region of MDR1, directly correlating with MDR1 upregulation. Specifically, drug-induced upregulation of MDR1 was associated with increases in H3 acetylation and induction of methylated H3K4 within discrete regions of the MDR1 locus. Our results demonstrate that chemotherapeutic drugs can actively induce epigenetic changes within the MDR1 promoter and enhance the MDR phenotype.

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Acknowledgements

We would like to thank Andrew Snowden and Peter Becker for reading the manuscript and helpful comments, David Huang for providing reagents and Katherine Hannan, Ross Hannan, Peter Laird and Gerhard Coetzee for helpful comments on developing the transcriptional activation assays. EKB was formerly supported by an APA scholarship and is a recipient of the Lyonel and Joanna Middows Fellowship. RWJ is a Wellcome Trust Senior Research Fellow. AE-O is a FRAXA Research Foundation Fellow and acknowledges the Hazel & Pip Appel Charitable Trust. This work is supported by a project grant from the National Health and Medical Research Council of Australia (NH&MRC), the Anti-Cancer Council of Victoria (ACCV) and the Wellcome Trust.

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  1. 4 These two authors contributed equally to this work

Authors and Affiliations

  1. Epigenetics in Human Health and Disease Laboratory, The Alfred Medical Research and Education Precinct (AMREP), Baker Medical Research Institute, Commercial Road, Prahran, Victoria, 3181, Australia

    Emma K Baker & Assam El-Osta

  2. Gene Regulation Laboratory, Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, Australia

    Ricky W Johnstone

  3. Department of Medical Oncology and Haematology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, Australia

    John R Zalcberg

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Baker, E., Johnstone, R., Zalcberg, J. et al. Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs. Oncogene 24, 8061–8075 (2005). https://doi.org/10.1038/sj.onc.1208955

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