The Sorrell lab has discovered that the Myc family of oncogenes is involved in coordinating cell survival and migration in both normal and cancer cells. Myc is essential for embryonic development and is hyper-activated in over 70 percent of human cancers where it drives tumor initiation and progression. Therefore, developing ways to specifically target the oncogenic functions of Myc may provide an important avenue to treat multiple types of malignancies.

To date, all studies have focused on Myc as a nuclear transcriptional driver of cell proliferation. Recently, our lab discovered an entirely new function of Myc that is independent of transcription. We found that a cytoplasmic form of Myc, named Myc-nick, drives cancer cell migration and survival in response cellular stress.

Our team showed that cancer cell survival and migration are stimulated by the acetylation of specific cytoplasmic proteins that is induced by a complex containing acetyltransferases and Myc-nick. Myc-nick-dependent acetylation of a-tubulin and ATG3 (autophagy related 3) promotes survival by increasing autophagy of cells exposed to hypoxia and starvation. Moreover, Myc-nick stimulates cell motility by promoting the expression of fascin and the activation of CDC42.

Myc is converted into Myc-nick by calpain proteases under stress conditions such as nutrient deprivation and hypoxia. Myc-nick promotes protein lysine acetylation, leading to cell and survival.

Our working model is that differences in tumor microenvironment lead to the generation of Myc-nick in the cytoplasm of sub-populations of cells. Myc-nick in turn increases survival of these cells by inducing autophagy and promotes cell motility by directly regulating the actin cytoskeleton. Based on our previous work, the conversion of Myc into Myc-nick functions as a molecular switch turning off cell proliferation and turning on a program that promotes cell survival and migration.

Model for Myc function and regulation in tumors