Abstract
We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N 2 -(1-carboxyethyl)-2'-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α-mediated transcription of NER genes via enhanced 2-ketoglutarate-dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.
Highlights
Individuals with type 2 diabetes (T2D) exhibit an increased incidence of cancers of the pancreas, liver, bladder, colon, breast, ovary, and endometrium (Giovannucci et al, 2010; Xu et al, 2014), with greater cancer-associated mortality relative to non-diabetic individuals (Seshasai et al, 2011)
Because genomic instability plays a significant role in the initiation and promotion of cancer (Vogelstein et al, 2013), we focused on defining mechanisms by which hyperglycemia contributes to DNA damage
HG culturing of nucleotide excision repair (NER)-deficient cells increased CEdG even further, 2.4-fold in CSB cells and 1.5-fold in Xeroderma Pigmentosum Group C (XPC) cells relative to levels measured in LG
Summary
Individuals with type 2 diabetes (T2D) exhibit an increased incidence of cancers of the pancreas, liver, bladder, colon, breast, ovary, and endometrium (Giovannucci et al, 2010; Xu et al, 2014), with greater cancer-associated mortality relative to non-diabetic individuals (Seshasai et al, 2011). Mechanisms linking diabetes and cancer have invoked the mitogenic and anti-apoptotic actions of insulin and insulin-like growth factor 1, increased cytokine secretion, steroid hormone dysregulation, chronic inflammation, and hyperglycemia (Khandwala et al, 2000; Braun et al, 2011; Xu et al, 2014; Gristina et al, 2015). In a 10-yr prospective cohort study, increasing levels of fasting plasma glucose were found to be an independent risk factor for elevated cancer risk and mortality (Jee et al, 2005). Cancer incidence was found to be significantly increased in non-insulin using diabetic individuals relative to those on insulin therapy, suggesting that the glucose lowering benefits of insulin outweigh its potential mitogenic effects (Yang et al, 2010). What clearly emerges from the results of these population-based approaches is the need for molecular studies to identify plausible mechanisms linking hyperglycemia to genomic instability and increased cancer susceptibility
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