An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Claudia Peitzsch; Monica Cojoc; Linda Hein; Ina Kurth; Katrin Mӓbert; Franziska Trautmann; Barbara Klink; Evelin Schrock; Manfred P Wirth; Mechthild Krause; Eduard A Stakhovsky; Gennady D Telegeev; Vladimir Novotny; Marieta Ioana 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 re-sensitize radioresistant prostate cancer cells

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

Cancer Research Unit

Research output: Contribution to journal › Article › peer-review

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
Early online date	16 Mar 2016
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-2116
Publication status	Published - 1 May 2016

Bibliographical note

Keywords

Animals
Blotting, Western
Cell Line, Tumor
Chromatin Immunoprecipitation
Comparative Genomic Hybridization
DNA Methylation/radiation effects
Epigenesis, Genetic/radiation effects
Flow Cytometry
Gene Expression Regulation, Neoplastic/radiation effects
Heterografts
Histones/genetics
Humans
Male
Mice
Mice, Nude
Microscopy, Fluorescence
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic/genetics
Prostatic Neoplasms/genetics
Radiation Tolerance/genetics
Radiotherapy
Retinal Dehydrogenase/genetics

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10.1158/0008-5472.CAN-15-2116

Cancer Res-2016-Peitzsch-0008-5472.CAN-15-2116
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Cite this

Peitzsch, C., Cojoc, M., Hein, L., Kurth, I., Mӓbert, K., Trautmann, F., Klink, B., Schrock, E., Wirth, M. P., Krause, M., Stakhovsky, E. A., Telegeev, G. D., Novotny, V., Toma, M. I., Muders, M., Baretton, G. B., Frame, F. M., Maitland, N. J., Baumann, M., & Dubrovska, A. (2016). An epigenetic reprogramming strategy to re-sensitize 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 re-sensitize 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.",

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Peitzsch, C, Cojoc, M, Hein, L, Kurth, I, Mӓbert, K, Trautmann, F, Klink, B, Schrock, E, Wirth, MP, Krause, M, Stakhovsky, EA, Telegeev, GD, Novotny, V, Toma, MI, Muders, M, Baretton, GB, Frame, FM , Maitland, NJ, Baumann, M & Dubrovska, A 2016, 'An epigenetic reprogramming strategy to re-sensitize 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 - Mӓbert, Katrin

AU - Trautmann, Franziska

AU - Klink, Barbara

AU - Schrock, Evelin

AU - Wirth, Manfred P

AU - Krause, Mechthild

AU - Stakhovsky, Eduard A

AU - Telegeev, Gennady D

AU - Novotny, Vladimir

AU - Toma, Marieta Ioana

AU - Muders, Michael

AU - Baretton, Gustavo B

AU - Frame, Fiona M

AU - Maitland, Norman J

AU - Baumann, Michael

AU - Dubrovska, Anna

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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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KW - Chromatin Immunoprecipitation

KW - Comparative Genomic Hybridization

KW - DNA Methylation/radiation effects

KW - Epigenesis, Genetic/radiation effects

KW - Flow Cytometry

KW - Gene Expression Regulation, Neoplastic/radiation effects

KW - Heterografts

KW - Histones/genetics

KW - Humans

KW - Male

KW - Mice

KW - Mice, Nude

KW - Microscopy, Fluorescence

KW - Oligonucleotide Array Sequence Analysis

KW - Promoter Regions, Genetic/genetics

KW - Prostatic Neoplasms/genetics

KW - Radiation Tolerance/genetics

KW - Radiotherapy

KW - Retinal Dehydrogenase/genetics

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U2 - 10.1158/0008-5472.CAN-15-2116

DO - 10.1158/0008-5472.CAN-15-2116

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C2 - 26984757

SN - 0008-5472

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SP - 2637

EP - 2651

JO - Cancer research

JF - Cancer research

IS - 9

ER -

An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Abstract

Bibliographical note

Keywords

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Norman James Maitland

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An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Abstract

Bibliographical note

Keywords

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Norman James Maitland

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