Editors' ChoiceCancer

Degrading the degrader to promote Wnt signaling

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Sci. Signal.  18 Aug 2015:
Vol. 8, Issue 390, pp. ec231
DOI: 10.1126/scisignal.aad2487

Aberrant activity of numerous pathways contributes to colon cancer, particularly the reactivation of developmental pathways, such as the Wnt pathway. The protein CSN6, a subunit of the COP9 signalosome that regulates ubiquitin-mediated protein degradation, is important for embryonic development. Fang et al. found that CSN6 indirectly stabilized the Wnt effector β-catenin, thereby promoting the growth of colorectal cancer (CRC). CSN6 abundance was increased in patient CRC tissue compared with adjacent normal mucosa and correlated with poor prognosis. Gene expression associated with the epidermal growth factor receptor (EGFR) pathway was enriched in samples with high abundance of CSN6. In cultured CRC cells, overexpressing constitutively active MEK1, a kinase in the mitogen-activated protein kinase (MAPK) pathway that is stimulated by EGFR, or adding EGF to the medium increased the abundance of CSN6 protein, but not mRNA, and decreased the ubiquitination of CSN6. In contrast, adding an inhibitor of MEK1 diminished the EGF-induced increase in CSN6 abundance. Coimmunoprecipitation assays showed that CSN6 interacted with ERK2, a kinase in the EGFR-stimulated MAPK pathway. Analysis of the effect of expressing CSN with a mutation in a site predicted to be phosphorylated by ERK showed that phosphorylation of CSN6 stabilized the protein and promoted proliferation in CRC cells. Overexpressing CSN6 dose-dependently increased the protein but not mRNA abundance of β-catenin as well as the expression of β-catenin target genes, and decreased the protein but not mRNA abundance of β-TrCP, a ubiquitin ligase that marks β-catenin for degradation. CSN6 interacted with and increased the ubiquitination and degradation of β-TrCP in transfected CRC cells. High abundance of CSN6 also correlated with high abundance of phosphorylated ERK and β-catenin in patient CRC samples. In mice bearing CRC xenografts, inhibiting EGFR with cetuximab suppressed growth and β-catenin target gene expression in tumors while increasing β-TrCP abundance. The findings suggest that inhibiting EGFR-MAPK-CSN6 pathway activity may suppress Wnt-driven CRC growth in patients.

L. Fang, W. Lu, H. H. Cho, S.-C. J. Yeung, J.-Y. Tung, C.-D. Hsiao, E. Fuentes-Mattei, D. Menter, C. Chen, L. Wang, J. Wang, M.-H. Lee, ERK2-dependent phosphorylation of CSN6 is critical in colorectal cancer development. Cancer Cell 28, 183–197 (2015). [PubMed]