Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response

Current address: German Human Genome-Phenome Archive; Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

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Current address: Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, 1090 Vienna, Austria.

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Current address: School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.

Academic Editors: Antonia Ávila-Flores and Pedro Torres-Ayuso

Cancers 2021, 13(10), 2455; https://doi.org/10.3390/cancers13102455

Received: 8 March 2021 / Revised: 4 May 2021 / Accepted: 12 May 2021 / Published: 18 May 2021

(This article belongs to the Special Issue Diacylglycerol Kinases in Cancer)

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To reduce long-term fibrosis risk after radiotherapy, we demonstrated with different experimental approaches that modulation of the epigenetic pattern at the DGKA enhancer can attenuate pro-fibrotic reactions in human fibroblasts. We used (epi)genomic editing of the DGKA enhancer and administration of various epigenetic drugs and were able to modulate radiation-induced expression of DGKA and pro-fibrotic collagens. Based on our results, clinical application of bromodomain inhibitors will open promising ways to epigenetically modulate DGKA expression and might provide novel therapeutic options to prevent or even reverse radiotherapy-induced fibrotic reactions.

Abstract

Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis. View Full-Text

Keywords: bromodomain inhibitors; DNA methylation; EZH2 inhibitors; radiotherapy-induced fibrosis

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MDPI and ACS Style

Liu, C.-S.; Toth, R.; Bakr, A.; Goyal, A.; Islam, M.S.; Breuer, K.; Mayakonda, A.; Lin, Y.-Y.; Stepper, P.; Jurkowski, T.P.; Veldwijk, M.R.; Sperk, E.; Herskind, C.; Lutsik, P.; Weichenhan, D.; Plass, C.; Schmezer, P.; Popanda, O. Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response. Cancers 2021, 13, 2455. https://doi.org/10.3390/cancers13102455

AMA Style

Liu C-S, Toth R, Bakr A, Goyal A, Islam MS, Breuer K, Mayakonda A, Lin Y-Y, Stepper P, Jurkowski TP, Veldwijk MR, Sperk E, Herskind C, Lutsik P, Weichenhan D, Plass C, Schmezer P, Popanda O. Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response. Cancers. 2021; 13(10):2455. https://doi.org/10.3390/cancers13102455

Chicago/Turabian Style

Liu, Chun-Shan, Reka Toth, Ali Bakr, Ashish Goyal, Md Saiful Islam, Kersten Breuer, Anand Mayakonda, Yu-Yu Lin, Peter Stepper, Tomasz P. Jurkowski, Marlon R. Veldwijk, Elena Sperk, Carsten Herskind, Pavlo Lutsik, Dieter Weichenhan, Christoph Plass, Peter Schmezer, and Odilia Popanda. 2021. "Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response" Cancers 13, no. 10: 2455. https://doi.org/10.3390/cancers13102455

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Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response

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