Regulation of the cell fate by DNA damage and hypoxia

Abstract

In order to provide the means for the design of novel rational anti-cancer drug therapies research efforts are concentrated on unravelling the molecular circuits which induce programmed cell death and block proliferation of cancer cells. Modern therapeutic strategies are based on the understanding of the complexity of physiological functions such as differentiation, development, immune responses, cell-cycle arrest, DNA damage repair, apoptosis, autophagy, energy metabolism, and senescence. It has become evident that this knowledge will provide the means to target the components of the pathways involved in these processes in a specific and selective manner thus paving the way for the development of effective and personalised anti-cancer therapies. Transcription is a crucial cellular process that regulates a multitude of physiological functions, which are essential in disease progression and cellular response to therapy. Transcription factors such as the p53 tumor suppressor and the hypoxia-inducible factor-α (HIF-α) are key players in carcinogenesis and cellular response to cancer therapies. Both of these transcription factors regulate gene expression of genes involved in cell death and proliferation, in some cases cooperating towards producing the same outcome and in some others mediating opposing effects. It is thus apparent that fine tuning of the activity of these transcription factors is essential to determine the cellular response to therapeutic regimens, in other words whether tumor cells will commit to apoptosis or evade engagement with the anti-proliferative effects of drugs leading to drug resistance. Our observations support the notion that the functional crosstalk between HIF-1α and p53 pathways and thus the fine tuning of their transcriptional activity is mediated by cofactors shared between the two transcription factors such as components of the p300 co-activator multiprotein complex. In particular, there is evidence to suggest that differential composition of the co-modulatory protein complexes associated with p53 and HIF-1α under diverse types of stress conditions differentially regulate the expression of distinct subsets of p53 and HIF-1α target genes involved in processes such as cell cycle arrest, apoptosis, chronic inflammation, and cellular energy metabolism thereby determining the cellular fate under particular types of micro-environmental stress.

Keywords: Cancer, Transcription, Apoptosis, Inflammation, Tumor energy metabolism, Glycolysis, Oxidative phosphorylation, p53, Hypoxia-inducible factor, p300/CBP associated factors

Core tip: The results of our work endorse the notion that specific features determine targeting of transcription factors to distinct clusters of their target genes including the nature of the DNA binding sites found within the regulatory region of the promoter of each one of the target genes, the composition of the cofactor network associated with different transcription factors under diverse types of stress conditions and the precise posttranslational modifications of each one of the transcription factors linking characteristic PTM codes with discrete types of micro-environmental stress. These features are essential considerations for the design of effective therapeutics and individualised cancer treatment.