Abstract 1249: The role of PRMT5 in MYC-driven medulloblastoma

Abstract

Abstract Medulloblastoma (MB) is the most common pediatric brain tumor, accounting for about 20% of all brain tumors in children. Children with Group 3 MB (aberrant MYC) show the worst prognosis, with <50% survival. Recently, the role and association of protein arginine methyl transferase (PRMT) 5 have been closely associated with aberrant MYC function in various cancers including other brain tumors such as glioblastoma. However, the role of PRMT5 and its association with MYC in MB have not been explored. Here we provide preliminary data indicating PRMT5 as a novel regulator of MYC and implicating PRMT5 as a potential therapeutic target in MYC-driven MB. Using cell lines, our results showed PRMT5 overexpression in MYC-driven MB compared to non-MYC MB. The results from co-immunoprecipitation experiment in MYC-driven MB cells demonstrated that MYC physically associates with PRMT5 by direct protein-protein interaction. In addition, cycloheximide chase experiment showed that PRMT5 regulates MYC stability. Knockdown of PRMT5 using siRNA in MYC-driven MB cells significantly decreased cell growth and MYC expression. We also tested the therapeutic potential of targeting PRMT5 against MB cell lines using a small molecule inhibitor EPZ015666. We observed a dose-dependent efficacy of EPZ015666 in suppressing cell growth in MYC-driven MB cell lines. We also observed a superior efficacy of this inhibitor against MYC-driven MB cells compared to non-MYC MB cells. Together, our results implicate the regulation of MYC oncoprotein by PRMT5, and suggest that targeting PRMT5 could be a potential therapeutic strategy for MYC-driven MB and other MYC-driven cancers. Citation Format: Nagendra K. Chaturvedi, Varun Kesherwani, Matthew J. Kling, Sutapa Ray, Timothy R. McGuire, Shantaram S. Joshi, J. Graham Sharp, Don W. Coulter. The role of PRMT5 in MYC-driven medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1249.