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

doi:10.1158/0008-5472.CAN-15-2116

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 journal › Article › Research › peer-review

62 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 language	English
Pages (from-to)	2637-2651
Number of pages	15
Journal	Cancer Research
Volume	76
Issue number	9
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-2116
Publication status	Published - 1 May 2016
Externally published	Yes

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Peitzsch, C., Cojoc, M., Hein, L., Kurth, I., Mäbert, K., Trautmann, F., Klink, B., Schröck, E., Wirth, M. P., Krause, M., Stakhovsky, E. A., Telegeev, G. D., Novotny, V., Toma, M., Muders, M., Baretton, G. B., Frame, F. M., Maitland, N. J., Baumann, M., & Dubrovska, A. (2016). An epigenetic reprogramming strategy to resensitize radioresistant prostate cancer cells. Cancer Research, 76(9), 2637-2651. https://doi.org/10.1158/0008-5472.CAN-15-2116

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title = "An epigenetic reprogramming strategy to resensitize radioresistant prostate cancer cells",

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.",

author = "Claudia Peitzsch and Monica Cojoc and Linda Hein and Ina Kurth and Katrin M{\"a}bert and Franziska Trautmann and Barbara Klink and Evelin Schr{\"o}ck and Wirth, {Manfred P.} and Mechthild Krause and Stakhovsky, {Eduard A.} and Telegeev, {Gennady D.} and Vladimir Novotny and Marieta Toma and Michael Muders and Baretton, {Gustavo B.} and Frame, {Fiona M.} and Maitland, {Norman J.} and Michael Baumann and Anna Dubrovska",

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doi = "10.1158/0008-5472.CAN-15-2116",

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Peitzsch, C, Cojoc, M, Hein, L, Kurth, I, Mäbert, K, Trautmann, F, Klink, B, Schröck, E, Wirth, MP, Krause, M, Stakhovsky, EA, Telegeev, GD, Novotny, V, Toma, M, Muders, M, Baretton, GB, Frame, FM, Maitland, NJ, Baumann, M & Dubrovska, A 2016, 'An epigenetic reprogramming strategy to resensitize radioresistant prostate cancer cells', Cancer Research, vol. 76, no. 9, pp. 2637-2651. https://doi.org/10.1158/0008-5472.CAN-15-2116

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AU - Peitzsch, Claudia

AU - Cojoc, Monica

AU - Hein, Linda

AU - Kurth, Ina

AU - Mäbert, Katrin

AU - Trautmann, Franziska

AU - Klink, Barbara

AU - Schröck, Evelin

AU - Wirth, Manfred P.

AU - Krause, Mechthild

AU - Stakhovsky, Eduard A.

AU - Telegeev, Gennady D.

AU - Novotny, Vladimir

AU - Toma, Marieta

AU - Muders, Michael

AU - Baretton, Gustavo B.

AU - Frame, Fiona M.

AU - Maitland, Norman J.

AU - Baumann, Michael

AU - Dubrovska, Anna

PY - 2016/5/1

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N2 - 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.

AB - 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.

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An epigenetic reprogramming strategy to resensitize radioresistant prostate cancer cells

Abstract

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