ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Biomarkers for predicting prognosis are critical to treating colorectal cancer (CRC) patients. We found that CSN6, a subunit of COP9 signalosome, is overexpressed in CRC samples and that CSN6 overexpression is correlated with poor patient survival. Mechanistic studies revealed that CSN6 is deregulated by epidermal growth factor receptor (EGFR) signaling, in which ERK2 binds directly to CSN6 Leu163/Val165 and phosphorylates CSN6 at Ser148. Furthermore, CSN6 regulated beta-Trcp and stabilized beta-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and beta-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuxinnab reduced colon cancer growth. Taken together, our study's findings indicate that the deregulation of beta-catenin by ERK2-activated CSN6 is important for CRC development.