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

• Type of Material: Article
• Authors: Hanwen Zhang, Emory University; Dan Zhu, Emory University; Zhaobin Zhang, Emory University; Stefan Kaluz, Emory University; Bing Yu, Emory University; Narra S. Devi, Emory University; Jeffrey Olson, Emory University; Erwin Van Meir, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41388-019-1036-7
• Title of Journal or Parent Work: ONCOGENE
• Volume: 39
• Issue: 5
• Start Page: 1041
• End Page: 1048
• Grant/Funding Information: This work was supported by grants from the NIH CA163722, CA235162, and NS096236 (to EGVM), CA138292 (to Winship Cancer Institute), the CURE Childhood Cancer Foundation and the St. Baldrick’s Foundation.
• Keywords: ANGIOGENESIS; Genetics & Heredity; P53; PROTEINS; Life Sciences & Biomedicine; Science & Technology; Cell Biology; Biochemistry & Molecular Biology; BRAIN; GENE; Oncology
• Research Categories: Health Sciences, Oncology; Biology, Genetics; Biology, Cell

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/EBPβ (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.