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

Chun Shan Liu, 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, Odilia Popanda*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)


Radiotherapy, a common component in cancer treatment, can induce adverse effects in-cluding 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 expres-sion. 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.

Original languageEnglish
Article number2455
Issue number10
Publication statusPublished - 2 May 2021
Externally publishedYes


  • Bromodomain inhibitors
  • DNA methylation
  • EZH2 inhibitors
  • Radiotherapy‐induced fi-brosis


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