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...

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Autores principales: 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
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Publicado: Nature Publishing Group 2021
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spelling oai:doaj.org-article:20c0c3f49a9e491b86d9b16315f3a86d2021-12-05T12:04:31ZDecreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments10.1038/s41419-021-04407-y2041-4889https://doaj.org/article/20c0c3f49a9e491b86d9b16315f3a86d2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04407-yhttps://doaj.org/toc/2041-4889Abstract 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.Iga K. MieczkowskaGaryfallia Pantelaiou-ProkakiEvangelos ProkakisGeske E. SchmidtLukas C. Müller-KirschbaumMarcel WernerMadhobi SenTaras VelychkoKatharina JannaschChristian DullinJoanna NappKlaus PantelHarriet WikmanMaria WieseChristof M. KrammFrauke AlvesFlorian WegwitzNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-13 (2021)
institution DOAJ
collection DOAJ
language EN
topic Cytology
QH573-671
spellingShingle Cytology
QH573-671
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
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.
format article
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
title 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_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_sort decreased prc2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments
publisher Nature Publishing Group
publishDate 2021
url https://doaj.org/article/20c0c3f49a9e491b86d9b16315f3a86d
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