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.
Highlights
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
To identify sites of differential DNA methylation associated with radiation-induced fibrosis risk, we screened 24 primary human dermal fibroblast samples derived from breast cancer patients receiving intraoperative radiotherapy (IORT; Supplementary Table 1)
We analysed fibroblasts isolated prior to treatment of breast cancer patients undergoing radiotherapy and identified DNA methylation differences in unirradiated fibroblasts, which were associated with fibrosis development after radiation
Summary
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. Radiation therapy is a common cancer treatment but the doses applied are often limited by the onset of adverse effects in the co-irradiated normal tissue. They can occur even months to years after radiotherapy and susceptibility differs widely among patients[1]. We identified DGKA as an epigenetically deregulated kinase involved in fibroblast activation after irradiation and stress exposure which has potential to serve as a therapeutic target for preventing radiation-induced fibrosis
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