Epigenetics in radiation-induced fibrosis

Abstract

Radiotherapy is a major cancer treatment option but dose-limiting side effects such as late-onset fibrosis in the irradiated tissue severely impair quality of life in cancer survivors. Efforts to explain radiation-induced fibrosis, for example, by genetic variation remained largely inconclusive. Recently published molecular analyses on radiation response and fibrogenesis showed a prominent role of epigenetic gene regulation. This review summarizes the current knowledge on epigenetic modifications in fibrotic disease and radiation response, and it points out the important role for epigenetic mechanisms such as DNA methylation, microRNAs and histone modifications in the development of this disease. The synopsis illustrates the complexity of radiation-induced fibrosis and reveals the need for investigations to further unravel its molecular mechanisms. Importantly, epigenetic changes are long-term determinants of gene expression and can therefore support those mechanisms that induce and perpetuate fibrogenesis even in the absence of the initial damaging stimulus. Future work must comprise the interconnection of acute radiation response and long-lasting epigenetic effects in order to assess their role in late-onset radiation fibrosis. An improved understanding of the underlying biology is fundamental to better comprehend the origin of this disease and to improve both preventive and therapeutic strategies.

Alterations in DNA methylation corresponding with lung inflammation and as a biomarker for disease development after MWCNT exposure

“…In confirmation of our hypothesis, DNA hypomethylation in the lungs as evidenced by both the LUMA and 5-mC assays was demonstrated following MWCNT exposure (Figure 7A and B). This is an important finding because it is critical to understand whether or not epigenetic alterations affecting gene expression following environmental exposures change lung DNA methylation and thus the lung environment, in a long-term manner (Weigel et al, 2015). This lasting alteration could increase the likelihood of disease development, including fibrosis, long after the initial response to the particle.…”

“…Aberrant epigenetic regulation, such as hyper- and hypo-methylation in promoter regions of specific genes, underlies a wide variety of pathologies, including cancer and cardiovascular disease (Martin et al, 2011; Webster et al, 2013). Fibrotic lung diseases have been shown to lead to epigenetic alterations within the lung (Sanders et al, 2012; Weigel et al, 2015). Exposure to fine particulate matter (PM) and ozone leads to alterations in DNA methylation of IFN-γ and other genes (Bind et al, 2014), implying that DNA methylation may play a role in inflammatory gene expression after inhalation exposures.…”

Radiation-induced fibrosis: mechanisms and implications for therapy

“…Mitochondrial DNA has been examined as well, and a genetic variant in TXNRD2 (thioredoxin reductase 2), which encodes a mitochondrial enzyme involved in the removal of reactive oxygen species (ROS), has been connected to rates of subcutaneous fibrosis (Edvardsen et al 2013). Lastly, epigenetic modifications to DNA and histones have been associated with RIF (Weigel et al 2014) as evidenced by the suppression of cutaneous radiation syndrome by histone deacetylase inhibitors (HDACs; Chung et al 2004). These types of DNA alterations are long term, and as such they likely play a significant role in the development of the chronic fibrotic response to radiation injury that persists even after the initial insult is no longer present.…”

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

“…Fibrosis has been well characterized through the study of many tissue-specific fibrotic diseases, including those of the lung (pulmonary fibrosis [5], radiation-induced lung fibrosis [6,7], and cystic fibrosis [8]), heart (endomyocardial fibrosis [9,10]), and liver (cirrhosis [11]). …”