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EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.

ABSTRACT: Medulloblastoma (MB) is a malignant pediatric brain tumor for which new therapies are urgently needed. We demonstrate that treatment with EPZ-6438 (Tazemetostat), an enhancer of zeste homolog 2 (EZH2) inhibitor approved for clinical trials, blocks MB cell growth in vitro and in vivo, and prolongs survival in orthotopic xenograft models. We show that the therapeutic effect is dependent on epigenetic reactivation of adhesion G-protein-coupled receptor B1 (BAI1/ADGRB1), a tumor suppressor that controls p53 stability by blocking Mdm2. Histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation is present at the ADGRB1 promoter, and inhibition of EZH2, the catalytic component of the Polycomb Repressive complex 2 (PRC2) that methylates H3K27, switches the gene into an active chromatin status and reactivates BAI1 expression. Mechanistically, targeting EZH2 promotes transition from H3K27me3 to H3K27ac at the promoter, recruits the C/EBP? (CREB-binding protein) and CBP transcription factors and activates ADGRB1 gene transcription. Taken together, our results identify key molecular players that regulate ADGRB1 gene expression in MB, demonstrate that reactivation of BAI1 expression underlies EPZ-6438 antitumorigenic action, and provide preclinical proof-of-principle evidence for targeting EZH2 in patients with MB.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7780546 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.

Zhang Hanwen H Zhu Dan D Zhang Zhaobin Z Kaluz Stefan S Yu Bing B Devi Narra S NS Olson Jeffrey J JJ Van Meir Erwin G EG

Oncogene 20191003 5

Medulloblastoma (MB) is a malignant pediatric brain tumor for which new therapies are urgently needed. We demonstrate that treatment with EPZ-6438 (Tazemetostat), an enhancer of zeste homolog 2 (EZH2) inhibitor approved for clinical trials, blocks MB cell growth in vitro and in vivo, and prolongs survival in orthotopic xenograft models. We show that the therapeutic effect is dependent on epigenetic reactivation of adhesion G-protein-coupled receptor B1 (BAI1/ADGRB1), a tumor suppressor that cont ...[more]

PMID: 31582835

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Project description:Background:Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene. Chemotherapy remains the standard of care for TNBC treatment, but considerable patients are very resistant to chemotherapy. Mutations or aberrant upregulation of EZH2 occur frequently, and EZH2 inhibitor (EZH2i) showed some preclinic antitumor effects in TNBC. Methods:RNA-seq data of 3 TNBC cell lines either treated with 2 ?M GSK343, or stably transduced with shEHZ2, compared to untreated controls (GSE112378) were analyzed by Limma R package. The Kaplan-Meier plotter (KM plotter) database was used to assess the relevance of FOSB mRNA expression to relapse-free survival (RFS) in TNBC. Cell number counting and colony formation assays were used to detect the biological effect of FOSB on the growth of TNBC cells in vitro. The effect of FOSB on TNBC tumor growth in vivo was investigated in a mice tumor xenograft model. Luciferase reporter and chromatin immunoprecipitation (Chip) assays were used to determine the regulatory roles of C/EBP? on FOSB expression. Results:We found that FOSB, a member of the activator protein-1 complex, was a direct downstream target of EZH2. FOSB was significantly decreased in TNBC samples and associated with better relapse-free survival (RFS). EZH2-mediated histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation, at the FOSB promoter inhibited it expression. Depletion of FOSB in TNBC cells promoted cell proliferation in vitro and tumor growth in vitro by inactivating the p53 pathway and conferred resistant to EZH2 inhibitor (EZH2i). Mechanistically, EZH2i promotes the shift from H3K27me3 to H3K27ac at the FOSB promoter, and recruits the transcription factor C/EBP? to activate FOSB gene transcription. Conclusion:Together, our results suggest that EZH2-mediated epigenetic inactivation of FOSB promotes TNBC expression and demonstrate that reactivation of FOSB expression by C/EBP? underlies the anti-TNBC action of EZH2is.

Dataset Information

EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.

Publications

EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.

Similar Datasets

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