Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis

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. Radiotherapy can induce fibrosis in cancer patients, limiting its use in clinical settings. Here, the authors identify a differentially methylated enhancer of the lipid kinase DGKA in fibroblasts from breast cancer patients developing fibrosis after radiotherapy and they show that DGKA inhibition affects lipid homeostasis and reduces pro-fibrotic fibroblast activation.