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Epigenetic modulation of radiation-induced diacylglycerol kinase alpha expression prevents pro-fibrotic fibroblast response

Liu, Chun-Shan, Toth, Reka, Bakr, Ali, Goyal, Ashish, Islam, Md Saiful, Breuer, Kersten, Mayakonda, Anand, Lin, Yu-Yu, Stepper, Peter, Jurkowski, Tomasz P., Veldwijk, Marlon R., Sperk, Elena, Herskind, Carsten, Lutsik, Pavlo, Weichenhan, Dieter, Plass, Christoph, Schmezer, Peter and Popanda, Odilia 2021. Epigenetic modulation of radiation-induced diacylglycerol kinase alpha expression prevents pro-fibrotic fibroblast response. Cancers 13 (10) , 2455. 10.3390/cancers13102455

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/
Publisher: MDPI
ISSN: 2072-6694
Date of First Compliant Deposit: 24 May 2021
Date of Acceptance: 12 May 2021
Last Modified: 25 May 2021 09:15
URI: https://orca.cardiff.ac.uk/id/eprint/141527

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