Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.

Michel Wassef,Christophe Le Tourneau,Philippe Chavrier,Marie Irondelle,Fabien Reyal,Aurélie Teissandier,Elisabetta Marangoni,Bertrand Ducos,Maud Kamal,Bruno Zeitouni,Raphaël Margueron,Matthieu Caron,Benjamin Sadacca,Michel Vidaud,Dider Meseure,Audrey Michaud,Margaux Charruel,Nicolas Servant,Silvia Fre,Nadège Gruel ,Verónica Rodilla ,Anne Vincent‐Salomon ,Éric Pasmant

doi:10.1101/gad.269522.115

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.

Highlights

Eukaryotic cells have developed sophisticated mechanisms to prevent or correct genetic mutations that could result in cell transformation
Given the prior links made between Ezh2 overexpression and the more aggressive forms of prostate cancer (Varambally et al 2002, 2008), we used genetically engineered mouse models of prostate cancer to investigate the role of the enzyme in carcinogenesis
H3K27me3 was heavily reduced in tumors lacking Ezh2 in 9- to 12-mo-old mice (Fig. 1B), invasive adenocarcinomas still formed with full penetrance (n = 6)

Summary

Introduction

Eukaryotic cells have developed sophisticated mechanisms to prevent or correct genetic mutations that could result in cell transformation. These mechanisms are often altered during tumor progression, leading to increased genome instability. More relevant to the present work, previous studies reported high levels of EZH2 in carcinomas such as prostate and breast cancer (Varambally et al 2002; Kleer et al 2003). In these tumor types, high levels of EZH2 are associated with advanced stages of cancer and poor prognosis. Overexpressed EZH2 was proposed to participate in aberrant silencing of tumor suppressor genes such as DAB2IP (Min et al 2010), ADRB2, and SLIT2

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Results

Conclusion