EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes

被引：5

作者：

Huang, Yeying ^{[1
]}

Durall, R. Taylor ^{[1
]}

Luong, Nhi M. ^{[1
]}

Hertzler, Hans J. ^{[1
]}

Huang, Julianna ^{[1
]}

Gokhale, Prafulla C. ^{[2
,3
]}

Leeper, Brittaney A. ^{[2
,3
]}

Persky, Nicole S. ^{[4
]}

Root, David E. ^{[4
]}

Anekal, Praju V. ^{[5
]}

Montero Llopis, Paula D. L. M. ^{[5
]}

David, Clement N. ^{[6
]}

Kutok, Jeffery L. ^{[7
]}

Raimondi, Alejandra ^{[7
]}

Saluja, Karan ^{[8
]}

Luo, Jia ^{[9
]}

Zahnow, Cynthia A. ^{[10
]}

Adane, Biniam ^{[11
]}

Stegmaier, Kimberly ^{[11
,12
]}

Hawkins, Catherine E. ^{[13
]}

Ponne, Christopher ^{[13
]}

Le, Quan ^{[13
]}

Shapiro, Geoffrey I. ^{[9
]}

Lemieux, Madeleine E. ^{[14
]}

Eagen, Kyle P. ^{[13
,15
,16
,17
,18
]}

French, Christopher A. ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[2] Dana Farber Canc Inst, Expt Therapeut Core, Boston, MA USA

[3] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA USA

[4] Broad Inst MIT & Harvard, Cambridge, MA USA

[5] Harvard Med Sch, MicRoN, Dept Microbiol, Boston, MA USA

[6] NanoString Technol Inc, Seattle, WA USA

[7] Epizyme Inc, Cambridge, MA USA

[8] Univ Texas Hlth Sci Ctr Houston, Dept Pathol & Lab Med, Houston, TX USA

[9] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[10] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA

[11] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA

[12] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA

[13] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX USA

[14] Bioinfo, Plantagenet, ON, Canada

[15] Baylor Coll Med, Ctr Precis Environm Hlth, Houston, TX USA

[16] Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX USA

[17] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX USA

[18] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX USA

来源：

CANCER RESEARCH | 2023年 / 83卷 / 23期

关键词：

SMALL-CELL CARCINOMA; MIDLINE CARCINOMA; TRANSCRIPTION FACTORS; BREAST-CANCER; OPEN-LABEL; BRD-NUT; MYC; INHIBITION; DIFFERENTIATION; METHYLATION;

D O I：

10.1158/0008-5472.CAN-23-1475

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. 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 in more 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. 3827Significance: 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

引用

页码：3956 / 3973

页数：18

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