Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

BACKGROUND: Translational reprogramming through controlled initiation from non-AUG start codons is considered a crucial driving force in tumorigenesis and tumor progression. However, its clinical impact and underlying mechanism are not fully understood. METHODS: Using a bioinformatics approach, we identified translation initiation regulator 5MP1/BZW2 on chromosome 7p as a potential oncogenic driver gene in colorectal cancer (CRC), and explored the biological effect of 5MP1 in CRC in vitro or in vivo. Pathway analysis was performed to identify the downstream target of 5MP1, which was verified with transcriptomic and biochemical analyses. Finally, we assessed the clinical significance of 5MP1 expression in CRC patients. FINDINGS: 5MP1 was ubiquitously amplified and overexpressed in CRC. 5MP1 promoted tumor growth and induced cell cycle progression of CRC. c-Myc was identified as its potential downstream effector. c-Myc has two in-frame start codons, AUG and CUG (non-AUG) located upstream of the AUG. 5MP1 expression increased the AUG-initiated c-Myc isoform relative to the CUG-initiated isoform. The AUG-initiated c-Myc isoform displayed higher protein stability and a stronger transactivation activity for oncogenic pathways than the CUG-initiated isoform, accounting for 5MP1-driven cell cycle progression and tumor growth. Clinically, high 5MP1 expression predicts poor survival of CRC patients. INTERPRETATION: 5MP1 is a novel oncogene that reprograms c-Myc translation in CRC. 5MP1 could be a potential therapeutic target to overcome therapeutic resistance conferred by tumor heterogeneity of CRC. FUND: Japan Society for the Promotion of Science; Priority Issue on Post-K computer; National Institutes of Health; National Science Foundation; KSU Johnson Cancer Center.