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Nat Commun. 2016 Mar 11;7:10893. doi: 10.1038/ncomms10893.

Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis.

Author information

1
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
3
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
4
Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
5
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
6
Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
7
Junior Research Group Biomarker Discovery, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
8
Biomarker Discovery, HI-STEM gGmbH, 69120 Heidelberg, Germany.
9
Instrumental Analytics and Bioanalytics, Technical University of Applied Sciences Mannheim, 68163 Mannheim, Germany.
10
German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.

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.

PMID:
26964756
PMCID:
PMC4792958
DOI:
10.1038/ncomms10893
[Indexed for MEDLINE]
Free PMC Article

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