EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes
Author:
Huang Yeying,Durall R. Taylor,Luong Nhi M.,Hertzler Hans J.,Huang Julianna,Gokhale Prafulla C.,Leeper Brittaney A.,Persky Nicole S.,Root David E.,Anekal Praju V.,Montero Llopis Paula D.L.M.,David Clement N.,Kutok Jeffery L.,Raimondi Alejandra,Saluja Karan,Luo Jia,Zahnow Cynthia A.,Adane Biniam,Stegmaier Kimberly,Hawkins Catherine E.,Ponne Christopher,Le Quan,Shapiro Geoffrey I.,Lemieux Madeleine E.,Eagen Kyle P.,French Christopher A.
Abstract
ABSTRACTNUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT’s ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes.CDKN2Awas identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort.STATEMENT OF SIGNIFICANCEIdentification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.
Publisher
Cold Spring Harbor Laboratory
Reference75 articles.
1. Chau NG , Ma C , Danga K , Al-Sayegh H , Nardi V , Barrette R , Lathan CS , DuBois SG , Haddad RI , Shapiro GI , Sallan SE , Dhar A , Nelson JJ , French CA . An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients. JNCI Cancer Spectr. 2020;4(2):pkz094.PMCID:7165803 2. Chau NG , Ma C , Danga K , Al-Sayegh H , Nardi V , Barrette R , Lathan CS , Dubois SG , Haddad RI , Shapiro GI , Sallan SE , Dhar A , Nelson JJ , French CA . An anatomical site and genetic based prognostic model for patients with NUT midline carcinoma: analysis of 124 patients. JNCI Cancer Spectrum. 2019 3. French CA , Cheng ML , Hanna GJ , DuBois SG , Chau NG , Hann CL , Storck S , Salgia R , Trucco M , Tseng J , Stathis A , Piekarz R , Lauer UM , Massard C , Bennett K , Coker S , Tontsch-Grunt U , Sos ML , Liao S , Wu CJ , Polyak K , Piha-Paul SA , Shapiro GI . Report of the First International Symposium on NUT Carcinoma Clinical cancer research : an official journal of the American Association for Cancer Research. 2022;Online ahead of print. 4. Stevens TM , Morlote D , Xiu J , Swensen J , Brandwein-Weber M , Miettinen MM , Gatalica Z , Bridge JA . NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2019 5. NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum. Modern pathology : an official journal of the United States and Canadian Academy of Pathology;Inc,2019
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