Marked for death: targeting epigenetic changes in cancer

Abstract

In the past few years, it has become clear that mutations in epigenetic regulatory genes are common in human cancers. Therapeutic strategies are now being developed to target cancers with mutations in these genes using specific chemical inhibitors. In addition, a complementary approach based on the concept of synthetic lethality, which allows exploitation of loss-of-function mutations in cancers that are not targetable by conventional methods, has gained traction. Both of these approaches are now being tested in several clinical trials. In this Review, we present recent advances in epigenetic drug discovery and development, and suggest possible future avenues of investigation to drive progress in this area.

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

“…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]. These alterations in the epigenetic marks on both DNA and proteins result in global changes of gene expression profiles that are linked to cancer development and progression [1,2,6]. However, unlike genetic mutations, epigenetic modifications are generally reversible.…”

“…ADD, Tudor, and WD40 domains), lysine acetylation (bromodomain, DBD, DPF, double PH domains), and serine/threonine phosphorylation (14-3-3 and BIR domains) [13,14]. Many epigenetic regulators are overexpressed, silenced, or mutated in cancer cells and act as drivers for cancer development [2]. Therefore, in recent years, there has been a significant amount of research both in academia and pharmaceutical companies aimed at modulating oncogenic epigenetic regulators to develop novel cancer therapeutics [2].…”

“…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].…”

“…However, over the past decade, mounting evidence has shown that epigenetic changes play crucial roles in tumor suppressor gene silencing, oncogene overexpression, and genome instability [1,2]. Epigenetic modifications are heritable changes within DNA, protein, or RNA that are not associated with direct mutations within genomic DNA sequences [1].…”

“…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]. These alterations in the epigenetic marks on both DNA and proteins result in global changes of gene expression profiles that are linked to cancer development and progression [1,2,6].…”