ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: an overview

ABSTRACT

Introduction: Members of the ATP-binding cassette (ABC) transmembrane transporters control the passage of several substrates across cell membranes, including drugs. This means that ABC transporters may exert a significant influence on the kinetics and dynamics of pharmacological agents, being responsible for the occurrence of multidrug-resistant (MDR) phenotype. Pharmacogenetic analyses have shed light on gene expression and polymorphisms as possible markers predictive of transporter activity. However, a non-negligible part of the variability in drug pharmacokinetics and pharmacodynamics still remains. Further research has demonstrated that different epigenetic mechanisms exert a coordinated control over ABC genes, and on the corresponding MDR phenotype.

Areas covered: DNA methylation and histone modifications (namely acetylation, methylation, phosphorylation, etc.) significantly impact gene expression, as well as noncoding RNA molecules that are involved in the post-transcriptional control of the ABC transporters ABCB1, ABCC1 and ABCG2. We describe the epigenetic mechanisms of gene expression control for ABC transporters and their relevant association with the MDR phenotype in human cancer.

Expert opinion: The clinical meaning of those observations is discussed in the review, highlighting the importance of the epigenetic control of the ABC transporters for the clinical therapeutic outcomes that despite their effects and applications, requires further investigation.

KEYWORDS:

• Epigenetics
• epigenomics
• ABC transporters
• MDR
• cancer

Article highlights

• Several anticancer drugs are substrate of ABC transmembrane transporters such as ABCB1, ABCC1 and ABCG2, whose variable activity may significantly influence treatment efficacy.

• The expression of abc genes is finely tuned by several epigenetic mechanisms, which have been found altered in many human cancers and associated with drug resistance phenotypes.

• The evaluation of noncoding RNA molecules, histone modifications and chromatin methylation could be useful to predict treatment efficacy and to check against the development of resistance phenotypes.

• Some of those evaluations may be done in the target tissues as well as in peripheral blood, hence increasing the number of patients who may benefit from these analyses.

• In turn, actual or potential targets for pharmacological treatments may be identified along the epigenetic processes that control gene expression, as well as histone deacetylases or miRNAs, opening new possibilities for cancer chemotherapies.

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Declaration of interest

A Di Paolo is an advisory board member for Novartis Farma SpA, Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.