Abstract 404: Function of Brg1 chromatin remodeling factor in sonic hedgehog-dependent medulloblastoma development

Abstract

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Overactive Shh signaling in cerebellum granule neuron precursors (CGNPs) is the leading cause of the childhood medulloblastoma (Shh-subtype). Previously we have shown that chromatin remodeler Brg1 is required for Shh target gene expression, and Brg1 deletion reduced CGNP proliferation in developing cerebellum. Current study focuses on the function of Brg1 in mouse model of Shh-subtype medulloblastoma. In CGNP cultured from SmoM2 transgenic mice where Shh pathway is constitutively active, we found Brg1 is required for CGNP mitogenic target gene expression and proliferation. In SmoM2 medulloblastoma cultures, we observed that tumor cell growth was inhibited by conditional knockout of Brg1. In subcutaneous transplantation, we found that tumors were significantly shrunk upon induction of Brg1 deletion. Detailed analysis indicated that Shh-dependent mitogenic target genes decreased by loss of Brg1. Further evidences showed that medulloblastoma cell proliferation was significant inhibited by conditional knockout of Brg1. Effect of Brg1 on the chromatin environment of target genes during medulloblastoma development will be discussed. Our study will provide insights to the epigenetic mechanism of Shh-dependent tumor development and new therapeutic targets. Citation Format: Xuanming Shi, Zilai Zhang, Qiu Wang, Jiang Wu. Function of Brg1 chromatin remodeling factor in sonic hedgehog-dependent medulloblastoma development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 404. doi:10.1158/1538-7445.AM2014-404