Abstract 3410: A novel regulatory region of the MYC oncogene decreases Myc transcriptional activity

MYC is a transcription factor that contributes to over 50% of cancers. While deregulated protein expression of MYC is an important factor driving tumorigenesis, remarkably little is known about the post-translational modifications (PTMs) that are necessary for MYC to function as an active oncogene. Given the important role of PTMs in the regulation of protein activity and stability, our overall objective is to further characterize novel PTMs of MYC, and the functional contribution of these modifications to the ability of the MYC to transform cells. Using a structure-function approach, we have identified six C-terminal lysines that can modulate the ability of MYC to transform cells. By utilizing lysine to arginine mutations (6KR) to abrogate signaling through these residues, we show that MYC 6KR increases anchorage-independent colony growth compared with MYC-WT. Moreover, this mutant was also more potent than WT in promoting xenograft tumour growth. Through target gene expression analysis and luciferase reporter assays, we show that 6KR has enhanced transcriptional activity compared with MYC-WT. To characterize the modifications that can occur at these lysine residues, we have performed mass spectrometry analysis and have identified a number of PTMs that can occur in this region. Furthermore, we have conducted BioID to identify MYC interactors that change in association with 6KR MYC compared to MYC-WT. We theorize that identifying the signaling pathways leading to post-translational modification of this region will be an important first step in the development of inhibitors targeting MYC induced transformation. Citation Format: Manpreet Kalkat, Amanda Wasylishen, Pak-Kei Michael Chan, Aleksandra Pandyra, Sam Sulgi Kim, Christina Bros, Brian Raught, Linda Z. Penn. A novel regulatory region of the MYC oncogene decreases Myc transcriptional activity. [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 3410. doi:10.1158/1538-7445.AM2014-3410