Cancer Epigenetics

Abstract

Epigenetic mechanisms establish cell type-specific gene expression patterns that are stably transmitted across cell divisions. Epigenetic changes in tumor cells reflect and contribute to their altered differentiation state. They arise by epimutations, secondary to altered cancer pathway activity, or through mutations in epigenetic regulators. This chapter provides an overview of epigenetic mechanisms in normal cell differentiation and their aberrations in cancer. DNA methylation changes in cancers comprise localized hypermethylation at CpG-islands, associated with gene silencing, and global hypomethylation across the genome. DNA methylation interacts with other epigenetic mechanisms to establish active and inactive chromatin states. Histone acetylation and deacetylation are respectively catalyzed by histone acetyltransferases and histone deacetylases to regulate gene expression. Polycomb and “trithorax-like” complexes regulate development and differentiation by modifying histones at enhancers and gene promoters. Cell type-specific enhancer activity patterns are crucial for differentiation and are established by networks of DNA-binding transcription factors acting together with chromatin-modifying and chromatin-remodeling epigenetic regulators. Many cancers harbor mutations in genes encoding epigenetic regulators, including DNA and histone methyltransferases, histone demethylases, histone acetyltransferases, and chromatin remodelers. Specific epigenetic mechanisms are involved in X-chromosome inactivation in female cells and in genomic imprinting. Aberrant genomic imprinting contributes to pediatric tumors but also carcinomas in adults. Special epigenetic states characterize stem cells. Cancer cells may acquire some of their properties, especially the ability for largely unlimited self-renewal, through epigenetic or genetic alterations. More generally, epigenetic deregulation confers increased plasticity to cancer cells.