High abundance of c-Jun is detected in invasive breast cancer cells and aggressive breast tumor malignancies. Here, we demonstrate that a major cause of high c-Jun abundance in invasive breast cancer cells is prolonged c-Jun protein stability owing to poor poly-ubiquitination of c-Jun. Among the known c-Jun-targeting E3 ligases, we identified constitutive photomorphogenesis protein 1 (COP1) as an E3 ligase responsible for c-Jun degradation in less invasive breast cancer cells because depletion of COP1 reduced c-Jun poly-ubiquitination leading to the stabilization of c-Jun protein. In a panel of breast cancer cell lines, we observed an inverse association between the levels of COP1 and c-Jun. However, overexpressing COP1 alone was unable to decrease c-Jun level in invasive breast cancer cells, indicating that efficient c-Jun protein degradation necessitates an additional event. Indeed, we found that glycogen synthase kinase 3 (GSK3) inhibitors elevated c-Jun abundance in less invasive breast cancer cells and that GSK3 beta nonphosphorylable c-Jun-T239A mutant displayed greater protein stability and poorer poly-ubiquitination compared to the wild-type c-Jun. The ability of simultaneously enforced expression of COP1 and constitutively active GSK3 beta to decrease c-Jun abundance in invasive breast cancer cells allowed us to conclude that c-Jun is negatively regulated through the coordinated action of COP1 and GSK3 beta. Importantly, co-expressing COP1 and active GSK3 beta blocked in vitro cell growth/migration and in vivo metastasis of invasive breast cancer cells. Gene expression profiling of breast tumor specimens further revealed that higher COP1 expression correlated with better recurrence-free survival. Our study supports the notion that COP1 is a suppressor of breast cancer progression.
[1]Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen, Fujian, Peoples R China.
[2]Georgia Regents Univ, Med Coll Georgia, Dept Biochem & Mol Biol, Augusta, GA 30912 USA.
[3]Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA.
[4]Georgia Regents Univ, Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA 30912 USA.
[5]Georgia Regents Univ, Dept Biostat, Augusta, GA 30912 USA.
[6]Shanghai Univ Tradit Chinese Med, Shanghai Municipal Educ Comm, E Inst, Shanghai, Peoples R China.
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