Chapter 9 - Targeting the Epigenome as a Therapeutic Strategy for Pancreatic Tumors: DNA and Histone Modifying Enzymes

Abstract

Pancreatic cancers, because of its highly aggressive nature, display one of the highest mortality rates. Further, this devastating disease is difficult to treat because of its late-stage diagnosis. Most research efforts have primarily focused on how genetic alterations lead to altered progression, contribute to diagnosis, and influence pancreatic cancer progression. However, none of these findings have turned into effective treatment for this dismal malignancy, and most patients cannot be treated by surgical resection. Both genetic and/or epigenetic perturbations are known to contribute toward the pathogenesis of pancreatic cancer. Indeed, the PDAC phenotype is defined by perturbations in epigenetic events, which drive the aberrant gene expression patterns and altered signaling from mutated oncogenes and tumor suppressors. Unlike mutations, epigenetic alterations are reversible. Given this feature of epigenetic mechanisms, it is conceivable to target epigenetic-based events that initiate, promote, and/or maintain pancreatic cancer. The conceptual understanding of the epigenetic perturbations could offer novel therapeutic avenues for treating patients affected with pancreatic cancer. In fact, extensive investigations are currently in progress for developing small-molecule inhibitors that could modify the epigenome in a reversible manner. In this new era of “epigenetic therapeutics,” the topics discussed herein could provide novel therapeutic and diagnostic approaches for this dismal disease to the medical community. The epigenetic processes can be divided mechanistically into the regulation of methylation of DNA, posttranslational modifications (PTMs) of histones, remodeling of nucleosomes, and transcriptional regulation or translation by noncoding RNAs. This chapter focuses on enzymes responsible for DNA and histone posttranslational modifications and the current knowledge we have on how these events are altered and their possible use as targets for epigenetic therapies during the pancreatic cancer progression.