EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer.

Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6075-6080. Epub 2019 Mar 13

Michel Wassef ¹ , Armelle Luscan ¹ , Setareh Aflaki ¹ , Dina Zielinski ² , Pascal W T C Jansen ³ ,

Michel Wassef ¹ , Armelle Luscan ¹ , Setareh Aflaki ¹ , Dina Zielinski ² , Pascal W T C Jansen ³ , H Irem Baymaz ³ , Aude Battistella ¹ , Carole Kersouani ¹ , Nicolas Servant ² , Margaret R Wallace ⁴ , Pierre Romero ¹ , Olivier Kosmider ⁵ , Pierre-Alexandre Just ⁶ , Mikaël Hivelin ⁷ , Sébastien Jacques ⁸ , Anne Vincent-Salomon ¹ , Michiel Vermeulen ³ , Michel Vidaud ⁹ , Eric Pasmant ⁹ , Raphaël Margueron ¹

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Author information

¹ INSERM U934/CNRS UMR3215, 75248 Paris, France.
² INSERM U900, Mines ParisTech, 75248 Paris, France.
³ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands.
⁴ Department of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610.
⁵ Institut Cochin, Department Development, Reproduction and Cancer, and Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre-Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.
⁶ Faculty of Medicine, Paris Descartes University, 75006 Paris, France.
⁷ Department of Plastic, Reconstructive, and Aesthetic Surgery, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
⁸ Genomic Platform, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, 75014 Paris, France.
⁹ Department of Molecular Genetics, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

摘要

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2's main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.

KEYWORDS: EZH2, Polycomb, cancer, chromatin

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