An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells
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...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2016-05, Vol.76 (9), p.2637-2651 |
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| creator | Peitzsch, Claudia Cojoc, Monica Hein, Linda Kurth, Ina Mäbert, Katrin Trautmann, Franziska Klink, Barbara Schröck, Evelin Wirth, Manfred P Krause, Mechthild Stakhovsky, Eduard A Telegeev, Gennady D Novotny, Vladimir Toma, Marieta Muders, Michael Baretton, Gustavo B Frame, Fiona M Maitland, Norman J Baumann, Michael Dubrovska, Anna |
| description | 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. Cancer Res; 76(9); 2637-51. ©2016 AACR. |
| doi_str_mv | 10.1158/0008-5472.CAN-15-2116 |
| format | Article |
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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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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. Cancer Res; 76(9); 2637-51. ©2016 AACR.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cell Line, Tumor</subject><subject>Chromatin Immunoprecipitation</subject><subject>Comparative Genomic Hybridization</subject><subject>DNA Methylation - radiation effects</subject><subject>Epigenesis, Genetic - radiation effects</subject><subject>Flow Cytometry</subject><subject>Gene Expression Regulation, Neoplastic - radiation effects</subject><subject>Heterografts</subject><subject>Histones - genetics</subject><subject>Histones - radiation effects</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Microscopy, Fluorescence</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Promoter Regions, Genetic - radiation effects</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Radiation Tolerance - genetics</subject><subject>Radiotherapy</subject><subject>Retinal Dehydrogenase - genetics</subject><subject>Retinal Dehydrogenase - radiation effects</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRS0EoqXwCaAs2aTYsR07yyoqD6kCVEBiZznOJDJqkmK7i_L1OCp0NTPynfHRQeia4DkhXN5hjGXKmcjm5eI5JTzNCMlP0JRwKlPBGD9F02Nmgi68_4ojJ5ifo0mWF5IJLqboc9Eny61toYdgTbKGrRtap7vO9m3yFpwO0O6TMMQXD723wf5Asta1HRx464PuQ_LqhtgESErdG3BJCZuNv0Rnjd54uPqrM_Rxv3wvH9PVy8NTuVilhmEZUl3ljBMjckYjkW5YVTNa0MivAUtTGE4JbSirG0awIQBcG9pklRCmMYxJOkO3h7sR_HsHPqjOehMJdA_DzisiCsxyWeAsRvkhaiKwd9CorbOddntFsBqlqlGYGoWpKFURrkapce_m74td1UF93Pq3SH8Bp1ZzXw</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Peitzsch, Claudia</creator><creator>Cojoc, Monica</creator><creator>Hein, Linda</creator><creator>Kurth, Ina</creator><creator>Mäbert, Katrin</creator><creator>Trautmann, Franziska</creator><creator>Klink, Barbara</creator><creator>Schröck, Evelin</creator><creator>Wirth, Manfred P</creator><creator>Krause, Mechthild</creator><creator>Stakhovsky, Eduard A</creator><creator>Telegeev, Gennady D</creator><creator>Novotny, Vladimir</creator><creator>Toma, Marieta</creator><creator>Muders, Michael</creator><creator>Baretton, Gustavo B</creator><creator>Frame, Fiona M</creator><creator>Maitland, Norman J</creator><creator>Baumann, Michael</creator><creator>Dubrovska, Anna</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20160501</creationdate><title>An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells</title><author>Peitzsch, Claudia ; 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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. 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| ispartof | Cancer research (Chicago, Ill.), 2016-05, Vol.76 (9), p.2637-2651 |
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| source | MEDLINE; American Association for Cancer Research Journals; EZB Electronic Journals Library |
| subjects | 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 Histones - radiation effects Humans Male Mice Mice, Nude Microscopy, Fluorescence Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic - genetics Promoter Regions, Genetic - radiation effects Prostatic Neoplasms - genetics Radiation Tolerance - genetics Radiotherapy Retinal Dehydrogenase - genetics Retinal Dehydrogenase - radiation effects |
| title | An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells |
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