Epigenetic Regulation of ABCB1 Transporter Expression and Function

Kerry      Reed; Amadeo   M.   Parissenti

Abstract

While the role of accumulations of mutations has been historically emphasized in the etiology of human cancers, converging evidence strongly implicates contributory epigenetic mechanisms as well. Recently, there have been accumulating observations on the role which epigenetics plays in the regulation of ABCB1 drug transporter expression and its ability to contribute to cancer incidence and multi-drug resistance (MDR) to a wide variety of therapeutic agents. As the development and use of epigenetic therapies for the prevention and treatment of cancer increase, the effect of these interventions on ABCB1 expression (and the related development of MDR) needs to be addressed. The potential for such agents and chemotherapy drugs to induce ABCB1 expression and drug resistance within the cancers they are attempting to treat or prevent is high. Thus, monitoring ABCB1 promoter methylation may be of particular importance when chemotherapy and epigenetic therapies are used, in particular if such agents induce ABCB1 expression. This information could improve our ability to distinguish between drug-sensitive tumours and MDR tumours. In addition, monitoring epigenetic changes within the promoters of ABCB1 and other genes implicated in chemotherapy resistance could help guide patient management by epigenetic agents and/or chemotherapy. The potential for monitoring dynamic changes in promoter methylation for genes associated with drug response using blood samples, rather than tumour core biopsies from cancer patients, makes this an extremely attractive approach for pharmacoepigenomics applications in the clinic.

Keywords: ABCB1, chemotherapy, DNA methylation, drug resistance, epigenetics, histone acetylation, MDR1, P-glycoprotein