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

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 and Odilia Popanda

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..

Medienart:	E-Artikel

Erscheinungsjahr:	18 May 2021 2021
Erschienen:	18 May 2021

Enthalten in:	Zur Gesamtaufnahme - volume:13
Enthalten in:	Cancers - 13(2021), 10 vom: Mai, Artikel-ID 2455, Seite 1-26

Sprache:	Englisch

Beteiligte Personen:	Liu, Chun-Shan [VerfasserIn] Toth, Reka [VerfasserIn] Bakr, Ali [VerfasserIn] Goyal, Ashish [VerfasserIn] Islam, Md Saiful [VerfasserIn] Breuer, Kersten [VerfasserIn] Mayakonda Thippeswamy, Anand, 1988- [VerfasserIn] Lin, Yu-Yu [VerfasserIn] Stepper, Peter [VerfasserIn] Jurkowski, Tomasz P. [VerfasserIn] Veldwijk, Marlon Romano, 1973- [VerfasserIn] Sperk, Elena, 1983- [VerfasserIn] Herskind, Carsten, 1952- [VerfasserIn] Lutsik, Pavlo [VerfasserIn] Weichenhan, Dieter [VerfasserIn] Plass, Christoph, 1961- [VerfasserIn] Schmezer, Peter [VerfasserIn] Popanda, Odilia [VerfasserIn]

Links:	Volltext [lizenzpflichtig] Volltext [lizenzpflichtig]

Themen:	Bromodomain inhibitors DNA methylation EZH2 inhibitors Radiotherapy-induced fibrosis

Anmerkungen:	Gesehen am 29.09.2021

Umfang:	26

doi:	10.3390/cancers13102455

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1772032441

Internformat


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