Suffocating cancer: hypoxia-associated epimutations as targets for cancer therapy

Here, we review the therapeutic potential of epigenetic modifications (including DNA methylation, histone modifications and miRNAs) occurring in hypoxia with particular reference to cancer and tumourigenesis.Control of cellular oxygen concentration is under strict regulation as hyperoxia causes damage secondary to reactive oxygen species and hypoxia leads to activation of a diverse array of downstream transcriptional pathways including angiogenesis, glucose metabolism and apoptosis.It is well understood that tumourigenesis is dependent on the development of microvasculature for micronutrient supply and oxygenation. As this vasculature develops in a chaotic way with structural malformations, regions of hypoxia are present within all solid tumours. Normal oxygen tension in healthy tissue is 7% (53 mmHg), levels of oxygenation in tumours may vary from physiological levels (7%) to severe hypoxia (< 1%) which is usually found in areas adjacent to necrotic tissue [1]. It has also been reported that within the same region of a given tumour, levels of oxygenation may cycle due to poor vasculature and limited oxygen diffusion, resulting in intermittent periods of hypoxia [1]. These cyclical episodes of hypoxia lead to increased metastatic potential of cancer cells [2].Cellular hypoxia is toxic, and when severe leads to cell death in both normal and cancerous cells. However, cancer cells have developed mechanisms through (epi)genetic modifications which allow them to survive and in some cases thrive in hypoxic conditions [3]. Preclinical studies have demonstrated that the selective pressure of tissue hypoxia drives the selective outgrowth of more aggressive tumour sub-clones [4]. In early stage lung cancer and pancreatic endocrine cancer markers of hypoxia have outperformed traditional histopathological staging for predicting prognosis [5,6].The direct observation of tumour hypoxia through oxygen electrode recording was first made over ten years ago [7]. This study demonstrat