Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments
Abstract Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping wi...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04407-y |
| _version_ | 1829465543760936960 |
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| author | Iga K. Mieczkowska Garyfallia Pantelaiou-Prokaki Evangelos Prokakis Geske E. Schmidt Lukas C. Müller-Kirschbaum Marcel Werner Madhobi Sen Taras Velychko Katharina Jannasch Christian Dullin Joanna Napp Klaus Pantel Harriet Wikman Maria Wiese Christof M. Kramm Frauke Alves Florian Wegwitz |
| author_facet | Iga K. Mieczkowska Garyfallia Pantelaiou-Prokaki Evangelos Prokakis Geske E. Schmidt Lukas C. Müller-Kirschbaum Marcel Werner Madhobi Sen Taras Velychko Katharina Jannasch Christian Dullin Joanna Napp Klaus Pantel Harriet Wikman Maria Wiese Christof M. Kramm Frauke Alves Florian Wegwitz |
| author_sort | Iga K. Mieczkowska |
| collection | DOAJ |
| description | Abstract Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2. Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC. |
| first_indexed | 2024-12-13T16:55:59Z |
| format | Article |
| id | doaj.art-20c0c3f49a9e491b86d9b16315f3a86d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-13T16:55:59Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-20c0c3f49a9e491b86d9b16315f3a86d2022-12-21T23:37:55ZengNature Publishing GroupCell Death and Disease2041-48892021-11-01121211310.1038/s41419-021-04407-yDecreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatmentsIga K. Mieczkowska0Garyfallia Pantelaiou-Prokaki1Evangelos Prokakis2Geske E. Schmidt3Lukas C. Müller-Kirschbaum4Marcel Werner5Madhobi Sen6Taras Velychko7Katharina Jannasch8Christian Dullin9Joanna Napp10Klaus Pantel11Harriet Wikman12Maria Wiese13Christof M. Kramm14Frauke Alves15Florian Wegwitz16Department of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gastroenterology, GI-Oncology and Endocrinology, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenClinic for Haematology and Medical Oncology, University Medical Center GöttingenTranslational Molecular Imaging, Max Planck Institute for Experimental MedicineTranslational Molecular Imaging, Max Planck Institute for Experimental MedicineInstitute of Tumor Biology, University Medical Center Hamburg-EppendorfInstitute of Tumor Biology, University Medical Center Hamburg-EppendorfDepartment of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center GöttingenDepartment of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center GöttingenTranslational Molecular Imaging, Max Planck Institute for Experimental MedicineDepartment of General, Visceral and Pediatric Surgery, University Medical Center GöttingenAbstract Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2. Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC.https://doi.org/10.1038/s41419-021-04407-y |
| spellingShingle | Iga K. Mieczkowska Garyfallia Pantelaiou-Prokaki Evangelos Prokakis Geske E. Schmidt Lukas C. Müller-Kirschbaum Marcel Werner Madhobi Sen Taras Velychko Katharina Jannasch Christian Dullin Joanna Napp Klaus Pantel Harriet Wikman Maria Wiese Christof M. Kramm Frauke Alves Florian Wegwitz Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments Cell Death and Disease |
| title | Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments |
| title_full | Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments |
| title_fullStr | Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments |
| title_full_unstemmed | Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments |
| title_short | Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments |
| title_sort | decreased prc2 activity supports the survival of basal like breast cancer cells to cytotoxic treatments |
| url | https://doi.org/10.1038/s41419-021-04407-y |
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