Abstract 2968: Interrogating the function of histone methyltransferases in MYC-driven medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor of the cerebellum, with four distinct molecular subgroups, each carrying different clinical prognoses. Group 3 (G3) is the most aggressive subgroup and is associated with amplifications of the MYC gene. MYC expression and function are controlled in part by epigenetic regulation, and interestingly, the few mutations that are found in G3 medulloblastoma are mostly located in genes encoding epigenetic regulators. Surprisingly, many tumors had no mutations raising the question as to whether non-mutated or non-amplified epigenetic regulators may be drivers of G3MB tumorigenesis. We previously found that dysregulation of the H3K27 methyltransferase EZH2 cooperates with MYC in G3MB, indicating that epigenetic regulators may provide a source of potential therapeutic targets. Therefore, to identify novel epigenetic drivers in G3MB, we performed an unbiased shRNA screen of 243 known chromatin regulators. The most intriguing candidate was SMYD3, a multidomain-containing protein with histone H4-lysine 5 (H4K5) methyltransferase activity. Knockdown of SMYD3 suppressed G3MB proliferation in vitro and tumor progression in vivo. SMYD3 protein is nuclear and associated with the MYC promoter. Deletion of SMYD3 results in loss of MYC, G2/M and epithelial-to-mesenchymal target gene expression. Using a multi-omics approach including CUT&RUN sequencing, RNA-seq, DNA methylation, cryo-electron microscopy (cryo-EM) and proteomics we aim to elucidate how SMYD3 controls G3MB tumorigenesis. These results highlight the role of a potentially targetable new epigenetic regulator of tumorigenesis in G3MB. Citation Format: Audrey L. Mercier, Jennifer L. Stripay, Silvija Bilokapic, Justin Williams, Stephanie Nance, Jingjing Liu, Steven Philips, Suresh Kandikonda, Marie Morfouace, Aude Bramoulle, Tamara Advedissian, Jiyang Yu, Junmin Peng, Aseem Ansari, Mario Halic, Adam Durbin, Christopher Vakoc, Martine F. Roussel. Interrogating the function of histone methyltransferases in MYC-driven medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2968.