Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.

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 from a 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.

• Authors: Michel Wassef, Veronica Rodilla, Aurélie Teissandier, Bruno Zeitouni, Nadege Gruel, Benjamin Sadacca, Marie Irondelle, Margaux Charruel, Bertrand Ducos, Audrey Michaud, Matthieu Caron, Elisabetta Marangoni, Philippe Chavrier, Christophe Le Tourneau, Maud Kamal, Eric Pasmant, Michel Vidaud, Nicolas Servant, Fabien Reyal, Dider Meseure, Anne Vincent-Salomon, Silvia Fre, Raphaël Margueron
• Journal: Genes & development (Genes Dev) Vol. 29 Issue 24 Pg. 2547-62 (Dec 15 2015) ISSN: 1549-5477 [Electronic] United States
• PMID: 26637281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wassef et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• Histones
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Ezh2 protein, mouse
• Polycomb Repressive Complex 2

Topics

• Animals
• Animals, Genetically Modified
• Breast Neoplasms (diagnosis, enzymology, genetics)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Enhancer of Zeste Homolog 2 Protein
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Histones (metabolism)
• Homeostasis (genetics)
• Humans
• Male
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Prognosis
• Prostatic Neoplasms (diagnosis, enzymology, genetics)