Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia

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.

Keywords: DNA methylation; epigenetic drugs; gene-repression; histone deacetylation; histone methylation; tumor hypoxia.

Figure 1

Epigenetic drugs in cancer therapy. A simplified schematic of the effects of DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) on cancer progression.

Figure 2

Tumor microenvironment and hypoxia. The majority of solid tumors are characterized by abnormal tumor vasculature. When the high rate of tumor growth cannot be sustained by tumor angiogenesis, this causes limited oxygen supply to the tumor cells distal to the blood vessels, forming regions of hypoxia. Hypoxic tumor cells exhibit increased aggressiveness and metastasis, and are resistant to radiation and chemotherapy.

Figure 3

Regulation of HIF family of transcription factors. HIF binds to hypoxia response elements (HRE) to activate transcription of the target genes. The HIF heterodimer is composed of a HIFα subunit and HIF1β subunit. HIFα is oxygen-sensitive and regulated by Prolyl-hydroxylases (PHD) and Factor Inhibiting HIF1 (FIH). In normoxia (at physiological oxygen levels) HIF1α is hydroxylated by PHD proteins leading to Von Hippel Lindau (VHL)-mediated ubiquitination of HIF1α and its subsequent degradation by the proteasome. In normoxia, FIH also mediates hydroxylation of HIF1α, preventing its interaction with p300/CBP, which is required for HIF-mediated transactivation. The oxygen-dependent PHDs and FIH are rendered inactive in hypoxic conditions leading to HIF1α stabilization. HIF1α stability also requires histone deacetylase (HDAC) activity, which can be blocked by HDAC inhibitors that lead to HIF1α destabilization. Under hypoxic stress, HIF1α is stabilized and it interacts with HIF1β and p300/CBP, and the complex binds to HRE to mediate transcriptional activation of hypoxia response genes, including BNIP3, LOX, VEGF, JmjC demethylases and TET1 hydroxylase. Although BNIP3 is a HIF target, DNA hypermethylation can block the HIF-mediated transcriptional activation of BNIP3. Although some JmjC demethylases and TET1 hydroxylase may be HIF targets, under severe hypoxia, certain members of these dioxygenase proteins may be rendered inactive due to their functional dependency on oxygen.