title: 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.
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Weigel
authors.affiliation: Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Veldwijk
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Seibold
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors.forename: Alla
authors.initials: A
authors.lastname: Slynko
authors.affiliation: Division of Preventive Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: David B
authors.initials: DB
authors.lastname: Liesenfeld
authors.affiliation: Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Mariona
authors.initials: M
authors.lastname: Rabionet
authors.affiliation: Junior Research Group Biomarker Discovery, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|Biomarker Discovery, HI-STEM gGmbH, 69120 Heidelberg, Germany.
authors.forename: Sabrina A
authors.initials: SA
authors.lastname: Hanke
authors.affiliation: Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Sperk
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Junior Research Group Biomarker Discovery, Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|Biomarker Discovery, HI-STEM gGmbH, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rösli
authors.affiliation: Lipid Pathobiochemistry Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|Instrumental Analytics and Bioanalytics, Technical University of Applied Sciences Mannheim, 68163 Mannheim, Germany.
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Yassen
authors.initials: Y
authors.lastname: Assenov
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.identifier: http://orcid.org/0000-0003-2554-3952
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Herskind
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Odilia
authors.identifier: http://orcid.org/0000-0002-5594-5736
authors.initials: O
authors.lastname: Popanda
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000532:radiotherapy*; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D019175:DNA Methylation / Q000235:genetics*; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D005355:Fibrosis / Q000209:etiology / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism*; D011832:Radiation Injuries / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D059467:Transcriptome
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D019852:Diacylglycerol Kinase