Cited by 196Drug Transport and Resistance MechanismsEpigenetics and DNA MethylationPharmacogenetics and Drug Metabolism

Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs

Baker, Emma K, Johnstone, Ricky W, Zalcberg, John R, El-Osta, Assam·2005·Oncogene

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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Crossref · 10.1038/sj.onc.1208955

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  • Epigenetic components, chromatin remodeling, transcriptional factors and survival signaling can contribute to the regulation of ABCB1 expression in cancer cells.

    “Studies have shown epigenetic components, chromatin remodeling (48), transcriptional factors (49) and survival signaling (50) all can contribute to the regulation of ABCB1 expression in cancer cells.”

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Authors
Baker, E. K., Johnstone, R. W., Zalcberg, J. R., & El-Osta, A.
Affiliations
  • The Alfred Hospital (AU)
  • Peter MacCallum Cancer Centre (AU)
Venue
Oncogene
Published
2005-08-08
Volume
24
Issue
54
Pages
8061-8075
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
OpenAlex
W2074803927
Cited by
196
References
47
Citations by year
2026: 3 · 2024: 2 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 8 · 2019: 2 · 2018: 7 · 2017: 9 · 2016: 15 · 2015: 13 · 2014: 11 · 2013: 19 · 2012: 13
FWCI
5.60
Type
journal article
Language
en
Open access
closed
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
MDR1 gene, multidrug resistance, P-glycoprotein, epigenetic regulation, chemotherapeutic drugs, promoter methylation, histone modifications, H3K4 methylation, histone H3 acetylation, transcriptional activation, post-transcriptional regulation, CpG methylation
MeSH terms
Acetylation, Antineoplastic Agents, Chromatin, Histones, Humans, Neoplasms, Promoter Regions, Genetic, Protein Processing, Post-Translational, Transcriptional Activation, Up-Regulation, Gene Expression Regulation, Neoplastic, Drug Resistance, Multiple, CpG Islands, Drug Resistance, Neoplasm, DNA Methylation, Genes, MDR, ATP Binding Cassette Transporter, Subfamily B, Member 1, Gene Silencing, Epigenesis, Genetic, Cell Line, Tumor, Chromatin Immunoprecipitation

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