TY - JOUR
T1 - EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes
AU - Huang, Yeying
AU - Durall, R. Taylor
AU - Luong, Nhi M.
AU - Hertzler, Hans J.
AU - Huang, Julianna
AU - Gokhale, Prafulla C.
AU - Leeper, Brittaney A.
AU - Persky, Nicole S.
AU - Root, David E.
AU - Anekal, Praju V.
AU - Llopis, Paula D.L.M.Montero
AU - David, Clement N.
AU - Kutok, Jeffery L.
AU - Raimondi, Alejandra
AU - Saluja, Karan
AU - Luo, Jia
AU - Zahnow, Cynthia A.
AU - Adane, Biniam
AU - Stegmaier, Kimberly
AU - Hawkins, Catherine E.
AU - Ponne, Christopher
AU - Le, Quan
AU - Shapiro, Geoffrey I.
AU - Lemieux, Madeleine E.
AU - Eagen, Kyle P.
AU - French, Christopher A.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - NUT carcinoma is an aggressive carcinoma driven by the BRD4- NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat 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. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting inmore pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth. Significance: Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827.
AB - NUT carcinoma is an aggressive carcinoma driven by the BRD4- NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat 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. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting inmore pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth. Significance: Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827.
UR - http://www.scopus.com/inward/record.url?scp=85178649202&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178649202&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-23-1475
DO - 10.1158/0008-5472.CAN-23-1475
M3 - Article
C2 - 37747726
AN - SCOPUS:85178649202
SN - 0008-5472
VL - 83
SP - 3956
EP - 3973
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -