Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis - Bio-informatique (CBIO) Access content directly
Journal Articles Genes and Development Year : 2015

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Audrey Michaud
  • Function : Author
  • PersonId : 1202756
Elisabetta Marangoni
Philippe Chavrier
Fabien Reyal
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  • PersonId : 911231
Anne Vincent-Salomon
Raphaël Margueron
  • Function : Author
  • PersonId : 1063067

Abstract

Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results froma tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2’s contribution to solid tumors with important therapeutic implications.
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Dates and versions

hal-02559123 , version 1 (07-06-2023)

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Michel Adam Wassef, Verónica Rodilla, Aurélie Teissandier, Bruno Zeitouni, Nadège Gruel, et al.. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. Genes and Development, 2015, 29 (24), pp.2547-2562. ⟨10.1101/gad.269522.115⟩. ⟨hal-02559123⟩
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