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

Cancer Cell. 2015 Aug 10;28(2):183-97. doi: 10.1016/j.ccell.2015.07.004.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • COP9 Signalosome Complex
  • Cell Line, Tumor
  • Cetuximab / pharmacology
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Female
  • Gene Expression Profiling
  • HCT116 Cells
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Ubiquitination
  • Xenograft Model Antitumor Assays / methods
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • COPS6 protein, human
  • beta Catenin
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • COP9 Signalosome Complex
  • Cetuximab

Associated data

  • GEO/GSE60697