TY - JOUR
T1 - ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development
AU - Fang, Lekun
AU - Lu, Weisi
AU - Choi, Hyun Ho
AU - Yeung, Sai Ching J.
AU - Tung, Jung Yu
AU - Hsiao, Chwan Deng
AU - Fuentes-Mattei, Enrique
AU - Menter, David
AU - Chen, Chuangqi
AU - Wang, Lei
AU - Wang, Jianping
AU - Lee, Mong Hong
N1 - Publisher Copyright:
© 2015 Elsevier Inc..
PY - 2015/8/10
Y1 - 2015/8/10
N2 - 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 β-Trcp and stabilized β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and β-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuximab reduced colon cancer growth. Taken together, our study's findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development. Fang et al. show that CSN6, a subunit of the COP9 signalosome, is overexpressed in human colorectal cancer (CRC) samples and correlates with poor patient survival. Deregulated CSN6 by EGFR signaling stabilizes β-catenin via blocking the ubiquitin-proteasome pathway, thereby promoting CRC development.
AB - 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 β-Trcp and stabilized β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and β-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuximab reduced colon cancer growth. Taken together, our study's findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development. Fang et al. show that CSN6, a subunit of the COP9 signalosome, is overexpressed in human colorectal cancer (CRC) samples and correlates with poor patient survival. Deregulated CSN6 by EGFR signaling stabilizes β-catenin via blocking the ubiquitin-proteasome pathway, thereby promoting CRC development.
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U2 - 10.1016/j.ccell.2015.07.004
DO - 10.1016/j.ccell.2015.07.004
M3 - Article
C2 - 26267535
AN - SCOPUS:84939459266
SN - 1535-6108
VL - 28
SP - 183
EP - 197
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -