Drug transporter regulation in tumors by DNA methylation

See research article http://www.genomemedicine.com/content/3/12/82 webciteDevelopment of hepatocellular carcinoma, in common with other types of tumor, is considered to be a multistep process. Genetic and epigenetic alterations accumulate in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes [1]. The concept that hepatocellular carcinoma is a disease of epigenetic as well as genetic alterations has been validated in the past two decades. The epigenetic pathway is, in contrast to the genetic events, a reversible alteration that is not caused by primary DNA sequence changes.There are three main epigenetic mechanisms: (i) hypermethylation of CpG islands in promoter sequences leading to silencing of tumor suppressor genes; (ii) DNA hypomethylation, which causes genomic instability or induction of genes involved, for example, in cell growth and invasion [2]; and (iii) histone modification, which affects chromatin conformation. Because epigenetic mechanisms may function as an interface between environmental factors and the genome [3], deregulation of the epigenome by environmental stressors (for example, hepatitis B and hepatitis C viruses, chronic alcohol intake, and aflatoxins) is believed to disrupt cellular processes and contribute to the risk of hepatocellular carcinoma. The early appearance of epigenetic changes makes them attractive targets for biomarker discovery. Moreover, drugs to reverse the epigenetic abnormalities are under development and some have already been approved. Cancer epigenetics is continuously translating into clinical practice and will help to optimize cancer diagnostics and treatment. The recent observation by Schaeffeler et al. in Genome Medicine that uptake transporters for anticancer drugs are epigenetically regulated in hepatocellular carcinoma adds an important piece of information to the growing body of research on cancer epigenetics [4]. The potential implications of these findings for