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EZH1/2 Function Mostly Within Canonical PRC2 and Exhibit Proliferation-Dependent Redundancy That Shapes Mutational Signatures in Cancer

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EZH1/2 Function Mostly Within Canonical PRC2 and Exhibit Proliferation-Dependent Redundancy That Shapes Mutational Signatures in Cancer EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer Michel Wassefa,b,1, Armelle Luscana,b,1, Setareh Aflakia,b, Dina Zielinskia,b,c, Pascal W. T. C. Jansend, H. Irem Baymazd, Aude Battistellaa,b, Carole Kersouania,b, Nicolas Servanta,c, Margaret R. Wallacee, Pierre Romeroa,b, Olivier Kosmiderf, Pierre-Alexandre Justg,h, Mikaël Hivelini,j, Sébastien Jacquesk, Anne Vincent-Salomona,b, Michiel Vermeulend, Michel Vidaudi,l, Eric Pasmanti,l,2, and Raphaël Marguerona,b,2 aInstitut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; bINSERM U934/CNRS UMR3215, 75248 Paris, France; cINSERM U900, Mines ParisTech, 75248 Paris, France; dDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands; eDepartment of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610; fInstitut Cochin, Department Development, Reproduction and Cancer, and Service d’Hématologie Biologique, Hôpitaux Universitaires Paris Centre–Cochin, Assistance Publique–Hôpitaux de Paris, 75014 Paris, France; gDepartment of Pathology, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique–Hôpitaux de Paris, 75014 Paris, France; hFaculty of Medicine, Paris Descartes University, 75006 Paris, France; iInstitut Cochin, INSERM U1016, Paris Descartes University, 75014 Paris, France; jDepartment of Plastic, Reconstructive, and Aesthetic Surgery, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, 75015 Paris, France; kGenomic Platform, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, 75014 Paris, France; and lDepartment of Molecular Genetics, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique–Hôpitaux de Paris, 75014 Paris, France Edited by Danny Reinberg, New York University School of Medicine, New York, NY, and approved February 20, 2019 (received for review August 24, 2018) Genetic mutations affecting chromatin modifiers are widespread in large B cell lymphoma, and a small subset of melanoma, while cancers. In malignant peripheral nerve sheath tumors (MPNSTs), functionally similar mutations affecting EZH1 have been found in Polycomb repressive complex 2 (PRC2), which plays a crucial role in autonomous thyroid adenomas. In contrast, recurrent loss-of- gene silencing, is inactivated through recurrent mutations in core function mutations in PRC2 genes occur in myeloid malignan- BIOCHEMISTRY subunits embryonic ectoderm development (EED) and suppressor of cies, T cell acute lymphoblastic leukemia (T-ALL), and malig- ’ zeste 12 homolog (SUZ12), but mutations in PRC2 s main catalytic nant peripheral nerve sheath tumors (MPNSTs) (7). subunit enhancer of zeste homolog 2 (EZH2) have never been found. MPNSTs are aggressive soft-tissue sarcomas that develop either This is in contrast to myeloid and lymphoid malignancies, which har- sporadically or from preexisting benign tumors called plexiform bor frequent loss-of-function mutations in EZH2. Here, we investi- neurofibromas in patients with neurofibromatosis type 1 (NF1) gated whether the absence of EZH2 mutations in MPNST is due to (Online Mendelian Inheritance in Man 162200). Previous studies a PRC2-independent (i.e., noncanonical) function of the enzyme or to have identified recurrent biallelic mutations in EED and SUZ12 redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 that result in a complete loss of H3K27me3 in over 50% of remains bound to EED but loses its interaction with all other core and MPNSTs (8–10). Loss of PRC2 function as well as co-occurring accessory PRC2 subunits. Through genetic and pharmacological anal- yses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, Significance we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that It is proposed that chromatin modifiers can regulate transcription the compensatory function of EZH1 is alleviated upon higher prolif- through different mechanisms sometimes referred as “canonical” eration. This work reveals how context-dependent redundancies can (toward chromatin) and “noncanonical” (toward other proteins). shape tumor-type specific mutation patterns in chromatin regulators. However, their relative contribution to the overall function of a given chromatin modifier is often enigmatic. We focused on the chromatin | cancer | Polycomb | EZH2 Polycomb complex PRC2 to investigate this question. Our results indicate that the canonical activity of PRC2 is largely pre- dominant, if not exclusive, and that the particular pattern of PRC2 t is estimated that over 25% of the most frequently mutated mutations in cancer is due to proliferation-dependent redun- genes in cancers encode chromatin regulators (1, 2). While I dancy between the two enzymatic subunits of the complex. some of these mutations are recurrent in a wide range of cancers, many others are found in specific tumor types, suggesting a context- Author contributions: M.W., A.L., M. Vidaud, E.P., and R.M. designed research; M.W., A.L., dependent function. This is well illustrated in the case of Polycomb S.A., P.W.T.C.J., H.I.B., A.B., C.K., and E.P. performed research; M.R.W., P.R., O.K., P.-A.J., repressive complex 2 (PRC2), a chromatin-modifying complex in- M.H., S.J., and A.V.-S. contributed new reagents/analytic tools; M.W., A.L., D.Z., P.W.T.C.J., volved in maintaining transcriptional repression. PRC2 contains H.I.B., N.S., M. Vermeulen, E.P., and R.M. analyzed data; and M.W., A.L., E.P., and R.M. wrote the paper. several essential subunits: embryonic ectoderm development (EED), suppressor of zeste 12 homolog (SUZ12), retinoblastoma-binding The authors declare no conflict of interest. protein 4/7 (RBBP4/7), and two paralogous enzymatic subunits en- This article is a PNAS Direct Submission. hancer of zeste homolog 1 and 2 (EZH1 and EZH2). EZH1 and Published under the PNAS license. EZH2 assemble into alternative PRC2 complexes with similar Data deposition: The data reported in this paper have been deposited in the Gene Ex- pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. composition that both catalyze methylation of lysine 27 on histone 3 GSE118186), and in the ProteomeXchange Consortium database via the PRIDE partner (H3K27) (3, 4). In addition, several accessory subunits associate with repository, https://www.ebi.ac.uk/pride/archive/ (dataset identifier PXD012547). PRC2, assist in its recruitment, and/or modulate its enzymatic ac- 1M.W. and A.L. contributed equally to this work. tivity (5). Methylation of H3K27 is essential for Polycomb-mediated 2To whom correspondence may be addressed. Email: [email protected] or silencing (6). Alterations of the PRC2 complex have been reported [email protected]. across different malignancies, and each alteration displays striking This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tumor type specificity (reviewed in ref. 7). Gain-of-function muta- 1073/pnas.1814634116/-/DCSupplemental. tions in EZH2 have been reported in follicular lymphoma, diffuse www.pnas.org/cgi/doi/10.1073/pnas.1814634116 PNAS Latest Articles | 1of6 Downloaded by guest on September 23, 2021 inactivation of NF1 and CDKN2A tumor suppressor genes are Results considered to be the most significant diagnostic markers of In the Absence of SUZ12, EZH2 Forms a Residual Complex with EED. MPNST in the revised World Health Organization 2016 classifi- To evaluate putative functions of EZH2 independent of an intact cation of tumors of the central nervous system (11). Surprisingly, PRC2 core complex, we first analyzed the biochemical properties of among 121 MPNST samples analyzed across five studies (8–10, 12, the enzyme in the context of loss of SUZ12. For this purpose, we 13), no mutations were detected in EZH1 or EZH2 despite the compared a SUZ12-mutated MPNST cell line (88-14) and a PRC2 high prevalence of lesions in EED and SUZ12. This mutation wild-type cell line (STS26T). EZH2 protein accumulation appears signature is in sharp contrast to the spectrum of PRC2 mutations much lower in the absence of SUZ12 (Fig. 1B,topWesternblot; found in myeloid malignancies and T-ALL, where mutations in compare signal in the input fraction), consistent with previous re- EZH2 occur at high frequency (Fig. 1A). The absence of muta- ports showing that PRC2 constituents stabilize each other (5). To tions in EZH1 and EZH2 in MPNST raises the possibility that the investigate the functionality of the residual EZH2 protein, we enzymatic subunits might have PRC2-independent functions that subjected nuclear extracts from 88-14 and STS26T to anion ex- are required for MPNST development. Several studies have in- change chromatography followed by size exclusion chromatography deed suggested that EZH1 and/or EZH2 can function in- (Fig. 1B). During anion-exchange chromatography, EZH2 elutes at dependently of their enzymatic activity within PRC2 (14–16). An 500 mM salt regardless of SUZ12 presence (Fig. 1B, Top). Fol- alternative reason for the absence of EZH2 and EZH1 mutations lowing size exclusion chromatography, EZH2 and EED coeluted in in MPNSTs might come from their potential
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