Stem cells, cancer, and epigenetics

The interest in cancer as an epigenetic, as well as a genetic disease, has markedly accelerated over the past decade. This chapter concentrates on one particularly interesting aspect of this – the growing evidence that one of the most studied epigenetic abnormalities in cancer, abnormal gene silencing associated with gene promoter DNA hypermethylation, is linked to key aspects of chromatin regulation of gene expression which maintains the state of embryonic stem (ES)/progenitor cells. This is a timely juxtaposition since there is also a growing body of data suggesting that cancer " stem/initiating cells " , especially when they may dominate in the most aggressive forms of human tumors, have a gene expression signature reminiscent of ES cells. A key part of this signature is an increase in polycomb protein group (PcG) complex constituents, and a decrease in expression of a group of genes for which PcG targeting is normally key to maintaining a poised, low basal activity, to maintain ES/progenitor cell status. A working hypothesis is explored that this primitive cell status in cancers may be, in part, maintained by a similar chromatin regulation of key genes with the addition, to many, of a fundamental abnormality, DNA methylation in CpG islands of the gene promoters. This DNA change is generally not a feature of the PcG targeted genes in ES/progenitor cells and may eliminate a prerequisite plasticity for these genes to ensure that their activation would normally allow lineage commitment and maturation. The early appearance of the DNA hypermethylation of at least a large group of genes in cancer development could reflect a key role for locking in a primitive state of abnormally expanding cells – which then provides an important substrate for the later changes that drive progression to invasive cancer. Copyright: C 2009 Stephen B. Baylin. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.