Epigenetic mechanisms in radiation-induced fibrosis

Fibrosis is an adverse effect of radiation therapy which occurs in 20-30% of patients even years after therapy. It is largely unpredictable and can severely impair quality of life. No efficient treatments are currently available to prevent or reverse fibrotic disease.Our recent findings strongly support the importance of epigenetic dysregulation in both radiation response and fibrotic processes. We developed cellular models for myofibroblast activation using dermal fibroblasts from breast cancer patients collected prior to irradiation. Using a genome-wide DNA methylation screen we identified differentially methylated regions (DMRs) of high interest which were associated with fibrosis and indicate new molecular mechanisms for radiation-induced fibrosis. As an example, we characterized one site as a differentially methylated enhancer of the diacylglycerol kinase alpha (DGKA) gene. Low DNA methylation at this enhancer enabled activation of profibrotic transcription factors and increased radiation-induced DGKA transcription specifically in cells from patients later developing fibrosis.

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We now aim to develop this novel mechanism further as a way to mitigate predisposition to fibrosis and to improve radiotherapy outcome in cancer survivors. Possible approaches are

  • modulating DGKAeffects by pharmacologically targeting the histone pattern at the DGKA enhancer with small molecules inhibiting epigenetic modifiers,
  • exploring further stress-inducible enhancers as potential players in key fibrotic processes such as short-term activation of fibroblast or perpetuation of the activates state in fibrotic tissue.

Results will contribute to the understanding of how regulatory genomic elements affect gene expression and how they are driven by epigenetics with the final goals of uncovering the epigenetic pathogenesis of fibrotic disease and using this knowledge for improving radiotherapy.

This work is done in collaboration with the Klinik für Strahlentherapie und Onkologie at the Universitätsmedizin Mannheim and funded by Deutsche Krebshilfe.

Publications:

Weigel C, Schmezer P, Plass C, Popanda O. Epigenetics in radiation-induced fibrosis. Oncogene. 2015 Apr 23;34(17):2145-55. doi: 10.1038/onc.2014.145. Epub 2014 Jun 9. Review. Abstract

Weigel C, Veldwijk MR, Oakes CC, Seibold P, Slynko A, Liesenfeld DB, Rabionet M, Hanke SA, Wenz F, Sperk E, Benner A, Rösli C, Sandhoff R, Assenov Y, Plass C, Herskind C, Chang-Claude J, Schmezer P, Popanda O. Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis. Nat Commun. 2016 Mar 11;7:10893. doi: 10.1038/ncomms10893. Abstract

Valinciute G, Weigel C, Veldwijk MR, Oakes CC, Herskind C, Wenz F, Plass C, Schmezer P, Popanda O. BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis. Radiother Oncol. 2017 Oct;125(1):168-174. doi: 10.1016/j.radonc.2017.08.028. Epub 2017 Sep 12. Abstract

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