Role of Methyltransferases in MYC-driven Medulloblastoma

Project Summary/Abstract Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages of 3 and 7. Based on extensive molecular evidence, medulloblastoma is classified into four major groups, among which Group (G3) MB with MYC overexpression, carry the worse prognosis. Thus, novel therapies are needed to effectively treat these aggressive brain tumors in children. Recent genome wide sequencing and 850K methylation profiling showed that G3MB has a paucity of mutations, most of which occur in epigenetic regulatory enzymes that modify histones. However, a significant proportion of MYC-driven G3 MBs do not harbor any mutations suggesting that additional non-mutated epigenetic regulators, so called “hidden drivers”, might act as oncogenes or tumor-suppressors, implicated in shaping the chromatin structure and driving G3 MB genesis. We performed a dropout shRNA screen of 243 unique mouse epigenetic regulators, and the top hit was SMYD3, a H4K5me1 methyltransferase that importantly regulates MYC expression. Systems biology reveals that SMYD3 is most overexpressed in G3 MBs that specifically overexpress MYC (type II) compared to the other G3 MB subtypes and MB Groups. To address the role of SMYD3 in driving G3 MB, we will use multiple complementary approaches in vitro and in vivo in both mouse and human G3MB to 1) assess how SMYD3 overexpression contributes to G3MB tumorigenesis, 2) use mass spectrometry to identify interacting proteins and define the role of SMYD3 in shaping the transcriptome, proteome and phosphoproteome, and 3) evaluate whether SMYD3 and other epigenetic regulators could be considered as therapeutic targets for future clinical trials in MYC-driven G3MB. Our ultimate goal is to identify epigenetic vulnerabilities that can be therapeutically targeted to treat the most aggressive forms of the disease.