Induction of DNA Hypomethylation by Tumor Hypoxia

Abstract

In cancer, the extensive methylation found in the bulk of chromatin is reduced, while the normally unmethylated CpG islands become hypermethylated. Regions of solid tumors are transiently and/or chronically exposed to ischemia (hypoxia) and reperfusion, conditions known to contribute to cancer progression. We hypothesized that hypoxic microenvironment may influence local epigenetic alterations, leading to inappropriate silencing and re-awakening of genes involved in cancer. We cultured human colorectal and melanoma cancer cell lines under severe hypoxic conditions, and examined their levels of global methylation using HPLC to quantify 5-methylcytosine (5-mC), and found that hypoxia induced losses of global methylation. This was more extensive in normal human fibroblasts than cancer cell lines. Cell lines from metastatic colorectal carcinoma or malignant melanoma were found to be markedly more hypomethylated than cell lines from their respective primary lesions, but they did not show further reduction of 5-mC levels under hypoxic conditions. To explore these epigenetic changes in vivo, we established xenografts of the same cancer cells in immune deficient mice. We used Hypoxyprobe to assess the magnitude of tissue hypoxia, and immunostaining for 5-mC to evaluate DNA methylation status in cells from different regions of tumors. We found an inverse relationship between the presence of extensive tumor hypoxia and the incidence of methylation, and a reduction of 5-mC in xenografts compared to the levels seen in the same cancer cell lines in vitro, verifying that methylation patterns are also modulated by hypoxia in vivo. This suggests that epigenetic events in solid tumors may be modulated by microenvironmental conditions such as hypoxia.

DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia

“…40 Although the cause of the epigenetic modification is unknown, it may be related to the hypoxic environment of the cells. 41,42 Intriguingly, TIMP3 expression was increased in the firsttrimester trophoblasts on hypoxic treatment. 43 This implies that the increased expression of TIMP3 under hypoxic condition, a hallmark in preeclamptic trophoblast, may be mediated by the epigenetic alteration on its promoter.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Changes in DNA methylation have been also associated with hypoxic conditions, including loss of global methylation in colorectal and melanoma cancer cell lines (Shahrzad et al, 2007). A recent example by Nanduri et al (2012) describes that intermittent hypoxia exposure in neonatal rats causes an exaggerated response to hypoxia associated with increased oxidative stress.…”

Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet

“…There are dynamic changes in the DNA methylation pattern during the lifetime and several environmental factors such as dietary compounds [12], oxidative stress [15], hypoxia [36], inflammation [37] or ageing [35] may affect methylation status and modify gene expression. Thus, changes in the DNA methylation pattern as a result of dietary treatments or conditions have been studied in the last years, comparing vegetarians with omnivores [39], the effects of different obesogenic diets [26,31] or different dietary treatments to lose weight [7].…”