Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis

Abstract

Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha (DGKA). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy.

Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

“…A methylation study of 18 candidate genes found a marginally significant association (P<0.05) between hypermethylation in the promoter region of the XRCC2 gene and late toxicity in cervical cancer patients treated with chemoradiotherapy (129). In the first genome-wide study of differential methylation, hypomethylation of an enhancer region in the gene coding for the signalling kinase DGKA (diacylglycerol kinase alpha) was found to be associated with the risk for developing late reaction (fibrosis) after adjuvant RT in patients treated with breast conserving therapy (130). It was shown that reduced methylation enabled radiation-induced transcription of DGKA and a fibrogenic response.…”

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

“…Thus far, all available cancer therapies can carry various side effects and lose effectiveness [5]. With the on-going increase in the number of cancer survivors, the prevention of radiotherapy-associated adverse effects has increasingly become a priority [6] ; [7]. Overall, the gastrointestinal (GI) syndrome is the main toxicity related to abdominal radiotherapy of human cancers [8].…”

Radiogenomics and radiotherapy response modeling

“…Effects of irradiation on DNA methylation, a key epigenetic mechanism regulating the expression of genetic information could be used to predict response (Miousse et al , 2017). Several studies have highlighted specific epigenetic variants and their impact on late toxicity (Weigel et al , 2016; Weigel et al , 2015). For instance, KDM3B has been shown to have a potential role on histone demethylation and radiosensitivity (Kerns et al , 2016).…”