Related Experiment Video
Updated: Jul 15, 2025
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes
Yeying Huang1, R Taylor Durall1, Nhi M Luong1
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract:
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. 3827.
Insights
Inhibiting EZH2, a gene silencing protein, shows promise for treating NUT carcinoma. Combining EZH2 and BET inhibitors synergistically blocks tumor growth and improves survival in preclinical models.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- NUT carcinoma is driven by the BRD4-NUT fusion oncoprotein, leading to aggressive tumor growth.
- BET bromodomain inhibitors (BETi) show limited efficacy as monotherapy for NUT carcinoma.
- Enhancer of zeste homolog 2 (EZH2) is identified as a key dependency in NUT carcinoma, responsible for gene silencing.
Purpose of the Study:
- To investigate the role of EZH2 in NUT carcinoma.
- To evaluate the efficacy of EZH2 inhibition, alone and in combination with BET inhibitors, for NUT carcinoma treatment.
Main Methods:
- Utilized the clinical compound tazemetostat to inhibit EZH2.
- Performed epigenetic and transcriptomic analysis to assess molecular changes.
- Conducted CRISPR-Cas9 screening to identify resistance mechanisms.
- Tested combined EZH2 and BET inhibition in preclinical NUT carcinoma models.
Main Results:
- Tazemetostat potently inhibited NUT carcinoma cell growth by reversing EZH2-mediated gene silencing.
- CDKN2A was identified as a key tumor suppressor gene repressed by EZH2 and conferring resistance to tazemetostat.
- Combined EZH2 and BET inhibition demonstrated synergistic effects, leading to pronounced tumor growth arrest and differentiation.
- Combined therapy significantly blocked tumor growth and prolonged survival in preclinical models, with complete remission observed in some cases.
Conclusions:
- EZH2 is a critical dependency in NUT carcinoma, highlighting the reliance on epigenetic dysregulation for tumor growth.
- Combining EZH2 and BET inhibitors offers a promising therapeutic strategy for NUT carcinoma by targeting complementary epigenetic pathways.
- Repression of tumor suppressor genes like CDKN2A by EZH2 provides a strong mechanistic basis for combination therapy.
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
02:33Hedgehog Signaling Pathway
02:23Abnormal Proliferation
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...