Abstract
In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing.
Highlights
Cancer EpigeneticsThe building blocks of chromatin are nucleosomes. Each nucleosome constitutes 146 base-pairs of DNA wound around a histone octamer consisting of histones H2A, H2B, H3 and H4
In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer
As DNA hypermethylation has been linked to cancer progression, clinical studies have focused on inhibitors of DNA methyltransferases (DNMT) as a potential therapeutic approach to reverse this cancer-promoting epigenetic change (Figure 1) [21,22]
Summary
The building blocks of chromatin are nucleosomes. Each nucleosome constitutes 146 base-pairs of DNA wound around a histone octamer consisting of histones H2A, H2B, H3 and H4. Nucleosomes are connected by linker DNA and the linker histone H1, extending the length of nucleosomal DNA to approximately 16–180 base-pairs This “beads on a string” arrangement of nucleosomes is further condensed into secondary and tertiary levels of compaction (the so-called 30 and 100 nanometer fibers), with progressively higher levels of compaction culminating in the familiar mitotic chromosome. Apoptosis-associated speck-like protein containing a CARD (ASC); and Suppressor of Cytokine Signaling (SOCS), can greatly contribute to cancer progression [13,14,15] The repression of these tumor suppressors was attributed to DNA hypermethylation and histone hypoacetylation [13,14,15]. Re-expressing the repressed or silenced tumor suppressors by pharmacologically reversing the cancer-associated epigenetic changes, may induce cancer cell death or sensitize the cancer cells to chemo- or radio-therapy [20], making epigenetic drugs a suitable approach to the treatment of cancer
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