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Upregulation of ABCG2 by romidepsin via the aryl hydrocarbon receptor pathway

Kenneth K W To1, Robert Robey, Zhirong Zhan

  • 1School of Pharmacy, The Chinese University of Hong Kong, Hong Kong. kennethto@cuhk.edu.hk

Molecular Cancer Research : MCR
|March 2, 2011
PubMed

Insights

Histone deacetylase inhibitors like romidepsin can upregulate ABCG2, a drug resistance transporter. This occurs via aryl hydrocarbon receptor (AhR) dissociation from Hsp90, potentially overcoming cancer therapy resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase inhibitors (HDACI) are investigated as anticancer agents, often in combination therapies.
  • Romidepsin, an HDACI, upregulates ABCG2 (a multidrug resistance transporter) in a cell line-specific manner.
  • The aryl hydrocarbon receptor (AhR) interacts with heat shock protein 90 (Hsp90) and regulates gene expression via xenobiotic response elements.

Purpose of the Study:

  • To elucidate the mechanism by which romidepsin induces cell line-specific upregulation of ABCG2.
  • To investigate the role of the aryl hydrocarbon receptor (AhR) and heat shock protein 90 (Hsp90) in romidepsin-mediated ABCG2 induction.

Main Methods:

  • Analysis of ABCG2 promoter activity and AhR binding in response to romidepsin.
  • Investigation of Hsp90 chaperone function and its interaction with AhR.
  • Assessment of Hsp70 acetylation and its effect on Hsp90-AhR complex.

Main Results:

  • Romidepsin treatment led to the dissociation of AhR from Hsp90 specifically in responsive cell lines.
  • This dissociation correlated with the upregulation of ABCG2 expression.
  • Romidepsin acetylated Hsp70, inhibiting Hsp90's chaperone activity towards AhR.

Conclusions:

  • Romidepsin-induced ABCG2 upregulation is mediated by the dissociation of AhR from Hsp90, a process influenced by Hsp70 acetylation.
  • This mechanism highlights a potential pathway for overcoming HDACI resistance in cancer treatment.
  • Understanding this differential ABCG2 regulation is crucial for optimizing HDACI-based cancer therapies.

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