Histone Modifications and Cancer

Abstract

Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics.

Epigenetics and Human Disease

“…Somatic epimutations are well documented in cancer as discussed in multiple articles in this collection, but particularly in Baylin and Jones (2014) and Audia and Campbell (2014). Here, the focus is on constitutional epimutations that affect most or all of the cells in an individual.…”

Targeting the epigenome in malignant pleural mesothelioma

“…Global DNA demethylation also results in de-repression of a variety of cancer-germline (CG) genes that are silent in normal somatic cells, yet exhibit stage-specific expression during germ cell development in testes or ovary (24). Simultaneous hypermethylation of tumor suppressors and hypomethylation of other genomic regions in cancer cells coincide with alterations in nucleosomal positioning, as well as modifications of core histones reflecting activated, repressed or bivalent chromatin structure within the respective loci (25).…”

“…Acetylation/deacetylation and methylation/demethylation have been the most extensively characterized histone modifications in normal and cancer cells (25,26). Histone acetylation is mediated by a variety of histone acetyltransferases (HATs) whereas histone deacetylation is mediated by HDACs that are divided into four classes [reviewed in ref (26)(27)(28)].…”

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

“…On the other hand, hypermethylation of CpG islands condenses chromatic structures and can inhibit tumor suppressor gene expression [3]. Aside from DNA methylation, another prominent epigenetic change in cancer is the aberrant modification of histones [6]. The genomic DNA is wrapped around histone proteins to form nucleosomes, and the acetylation, methylation, phosphorylation, ubiquitination, and sumoylation of various histone tails (the 'histone code') regulate the chromatin structure, transcription factor binding, and gene expression of any genomic locus [1,2,6].…”

“…Aside from DNA methylation, another prominent epigenetic change in cancer is the aberrant modification of histones [6]. The genomic DNA is wrapped around histone proteins to form nucleosomes, and the acetylation, methylation, phosphorylation, ubiquitination, and sumoylation of various histone tails (the 'histone code') regulate the chromatin structure, transcription factor binding, and gene expression of any genomic locus [1,2,6]. Cancer cells harbor abnormal histone modifications due to the mutation, silencing, or overexpression of various epigenetic regulator proteins that are responsible for the reading, writing, or erasing of histone marks associated with normal cell function [1,2].…”