An epigenetic reprogramming strategy to resensitize radioresistant prostate cancer cells

Claudia Peitzsch, Monica Cojoc, Linda Hein, Ina Kurth, Katrin Mäbert, Franziska Trautmann, Barbara Klink, Evelin Schröck, Manfred P. Wirth, Mechthild Krause, Eduard A. Stakhovsky, Gennady D. Telegeev, Vladimir Novotny, Marieta Toma, Michael Muders, Gustavo B. Baretton, Fiona M. Frame, Norman J. Maitland, Michael Baumann, Anna Dubrovska*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

45 Citations (Scopus)

Abstract

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations.

Original languageEnglish
Pages (from-to)2637-2651
Number of pages15
JournalCancer Research
Volume76
Issue number9
DOIs
Publication statusPublished - 1 May 2016
Externally publishedYes

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