suffocating cancer hypoxia-associated epimutations as targets for cancer therapy令人窒息的癌症hypoxia-associated表突变作为癌症治疗的目标.pdfVIP

Thirlwell et al. Clinical Epigenetics 2011, 3:9 /content/3/1/9 REVIEW Open Access Suffocating cancer: hypoxia-associated epimutations as targets for cancer therapy * C Thirlwell , LKE Schulz, HK Dibra and S Beck Abstract Lower than normal levels of oxygen (hypoxia) is a hallmark of all solid tumours rendering them frequently resistant to both radiotherapy and chemotherapy regimes. Furthermore, tumour hypoxia and activation of the hypoxia inducible factor (HIF) transcriptional pathway is associated with poorer prognosis. Driven by both genetic and epigenetic changes, cancer cells do not only survive but thrive in hypoxic conditions. Detailed knowledge of these changes and their functional consequences is of great clinical utility and is already helping to determine phenotypic plasticity, histological tumour grading and overall prognosis and survival stratification in several cancer types. As epigenetic changes - contrary to genetic changes - are potentially reversible, they may prove to be potent therapeutic targets to add to the cancer physicians’ armorarium in the future. 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. Keywords: Hypoxia, Hypoxia inducible factor (HIF), DNA methylation, histone modification, micro-RNA Introduction Cellular hypoxia is toxic, and when severe leads to cell Tumour hypoxia - a regulatory factor in tumour growth death in both normal and cancerous cells. However, can- Control of cellular oxygen concentration is under strict cer cells have developed mechanisms through (epi)genetic regulation as hyperoxia causes damage