Stress-induced cleavage of Myc promotes cancer cell survival

• Published in: Genes & development 2014-04, Vol.28 (7), p.689-707
• Main Authors: Conacci-Sorrell, Maralice, Ngouenet, Celine, Anderson, Sarah, Brabletz, Thomas, Eisenman, Robert N
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Antineoplastic Agents - pharmacology; Autophagy - genetics; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Colonic Neoplasms - pathology; Colonic Neoplasms - physiopathology; Cytoplasm - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomic Instability - genetics; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Proteolysis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Research Paper; Stress, Physiological - physiology
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.231894.113

Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy. Myc-nick also delays colon cancer cell death after treatment with chemotherapeutic drugs such as etoposide, cisplatin, and imatinib. Furthermore, colon cancer cells expressing a cleavage-resistant form of Myc undergo extensive apoptosis but are rescued by overexpression of Myc-nick. We also found that ectopic expression of Myc-nick results in the induction of the actin-bundling protein fascin, formation of filopodia, and increased cell motility-all mediators of tumor metastasis. Myc-nick-induced survival, autophagy, and motility require Myc box II (MBII), a region of Myc-nick that recruits acetyltransferases that in turn modify cytoplasmic proteins, including α-tubulin and ATG3. Our results suggest that Myc-nick-induced survival and motility contribute to colon cancer progression and metastasis.