Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis

Christoph Weigel, Marlon R. Veldwijk, Christopher C. Oakes, Petra Seibold, Alla Slynko, David B. Liesenfeld, Mariona Rabionet, Sabrina A. Hanke, Frederik Wenz, Elena Sperk, Axel Benner, Christoph Rösli, Roger Sandhoff, Yassen Assenov, Christoph Plass, Carsten Herskind, Jenny Chang-Claude, Peter Schmezer, Odilia Popanda

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.