ArticleCancer research2023
EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Histone modifications across cancers: mechanisms, therapy and clinical translation.Molecular cancer · 2026Review
- Article
- Shared PRAME epitopes are T-cell targets in NUT carcinoma.Journal for immunotherapy of cancer · 2026Article
- Exploring the role of EZH2 in neuroinflammation: implications for innovative therapeutic strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- International guidelines on the diagnosis and treatment of NUT carcinoma.Innovation (Cambridge (Mass.)) · 2026Review
- Targeting oncogenic fusion-driven NUT carcinoma with CRISPR-Cas9 genome editing.Molecular therapy. Oncology · 2025Article
- EZH2 confers lenvatinib resistance in hepatocellular carcinoma by suppressing ACSL1-Mediated ferroptosis.BMC cancer · 2025Article
- Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck.Nature reviews. Clinical oncology · 2025Review
- NUT carcinoma of the head and neck: A case report and literature review.Precision radiation oncology · 2024Review
- The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma.Cancer research · 2023Article
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26 authors at 11 institutions in 2 countries.
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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.
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