Abstract 5423: Lysine-52 stabilizes the MYC oncoprotein through a SCFFBXW7-independent mechanism

The oncogenic transcription factor c-MYC (MYC) is deregulated, and often overexpressed, in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would dramatically impact patient care and outcome. MYC is a highly regulated transcription factor, with a protein and mRNA half-life of approximately 30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCF FBXW7 . Here we provide evidence for a SCF FBXW7 -independent regulatory mechanism centered on Lysine 52 (K52) within MYC Box I (MBI) of the MYC protein. This residue has been shown to be post-translationally modified by both ubiquitylation and SUMOylation, hinting at the interplay of post-translational modifications at this site, and the importance of this residue. We demonstrate that mutation of K52 to arginine (R) renders the MYC protein more labile. Mechanistically, we show that the degradation pathway regulated by K52 is independent of the Cullin-Ring-Ligase (CRL) family of E3-ligases, which includes not only the canonical SCF FBXW7 , but also a number of other known MYC-targeting E3-ligases, such as SCF SKP2 , SCF βTCRP , SCF FBXO28 and DCX TRUSS . To characterize this degradation pathway further we will utilize unbiased and targeted experiments to elucidate the proteins involved. Taken together, our data identifies a novel regulatory pathway centred on K52 that may be exploited for the development of anti-MYC therapeutics. Citation Format: Jason De Melo, Sam S. Kim, Corey Lourenco, Diana Resetca, Maria Sunnerhagen, Brian Raught, Linda Z. Penn. Lysine-52 stabilizes the MYC oncoprotein through a SCF FBXW7 -independent mechanism [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 5423.