Abstract IA06: Recycling Myc to survive stress
Authors: Conacci-Sorrell Maralice , Ngouenet Celine , Anderson Sarah , Eisenman Robert 
Published: October 2015

Abstract
Missexpression of Myc family members has been linked to numerous abnormalities ranging from developmental defects to cancer. Indeed there is considerable evidence that Myc expression is controlled at every level of gene regulation, including protein degradation. Recently we found that Myc is targeted by calcium-dependent cytosolic proteases from the calpain family. Unlike proteasomal degradation resulting in complete protein destruction, calpain mediated proteolysis leads to partial cleavage of substrates. While regulated calpain activity is essential for embryonic development and terminal differentiation, aberrant calpain levels and activity have been correlated with tumor development and metastasis.
We found that upon calpain cleavage, the C-terminus of Myc is degraded, while an N-terminal segment of about 300 aminoacids is preserved and gives rise to Myc-nick. The removal of the C-terminus of Myc, which is essential for nuclear translocation and to binding to DNA and to Max, renders Myc-nick transcriptionally inactive and cytoplasmically localized. The conversion of Myc into Myc-nick is significantly enhanced in cancer cells exposed to stress conditions such as hypoxia and nutrient deprivation. Importantly, we found that Myc-nick expression increases the survival of colon cancer cells following nutrient deprivation, hypoxia, and treatment chemotherapeutic agents such as etoposide, cisplatin and imatinib. Myc-nick expressing cells display an increase in autophagy and treatment with inhibitors of autophagy prevents cell survival. Therefore, we propose that activation of autophagy is the major mechanism by which Myc-nick promotes cell survival under adverse conditions and drug treatment. The ability of Myc-nick to augment autophagy and cell survival requires its binding to acetyltransferases which correlates with acetylation of cytoplasmic proteins. We find that Myc-nick augments acetylation of ATG3 and alpha-tubulin, which are required in the acetylated form for the migration of autophagosomes and their subsequent fusion with lysosomes.
Overexpression of Myc-nick not only promotes the survival of colon cancer cells, but also increases their motility. Importantly, Myc-nick induces an increase in the formation of filopodia and the expression of fascin, which is a robust driver of invasiveness in solid tumors. Myc-nick expressing cells, while highly motile, do not appear to undergo epithelial to mesenchymal transition (EMT). These cells migrate while maintaining their epithelial shape by making use of very distinct filopodia. This is likely to be related to the recently described phenomenon called “collective invasion”, where cancer cells become invasive in the absence of EMT. Our results indicate that Myc-nick-induced survival and motility play important roles in promoting the progression of Myc-dependant tumors.
Citation Format: Maralice Conacci-Sorrell, Celine Ngouenet, Sarah Anderson, Robert Eisenman. Recycling Myc to survive stress. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA06.