Abstract LB-206: Inhibition of MYC by the SMARCB1 tumor suppressor

Abstract

Abstract The SMARCB1 tumor suppressor (SNF5) is a known interaction partner of the oncoprotein c-MYC (MYC), and thought to serve as a co-activator of its transcriptional properties. This role of SNF5, however, is at odds with the tumor suppressor function of SNF5, and with findings that loss of SNF5 is associated with activation of MYC target gene signatures. We have used biochemical, genetic, and genome-wide approaches to reexamine the relationship of SNF5 with MYC within the context of malignant rhabdoid tumor (MRT), an aggressive childhood cancer in which SNF5 is lost. We find that, consistent with activation of MYC target gene signatures in tumors that lack SNF5, MYC function is important for multiple aspects of MRT biology. Surprisingly, SNF5 is capable of inhibiting MYC binding to E boxes in vitro and globally within the context of chromatin. Using ATAC-seq, RNA-seq, and PRO-Seq, we demonstrate that regulation of MYC binding by SNF5 is independent of the role of SNF5 in chromatin remodeling, but instead is responsible for controlling RNA polymerase pause release at MYC-regulated genes. These findings inform a novel model of MRT tumorigenesis in which loss of SNF5 derepresses MYC function, raising the possibility that MYC contributes to disease progression in this malignancy. Citation Format: April M. Weissmiller, Jing Wang, Shelly L. Lorey, Gregory C. Howard, Ernest Martinez, Qi Liu, William P. Tansey. Inhibition of MYC by the SMARCB1 tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-206.