A gene signature consisting of ubiquitin ligases and deubiquitinating enzymes of SKP2 is associated with clinical outcome in breast cancer

Abstract

Abstract The ubiquitination of SKP2, an oncoprotein, is controlled by its E3 ligases, including APC/CFZR1 and deubiquitinases such as USP10. We identified a two-gene signature for the ubiquitination of SKP2, consisting of the copy number of FZR1 compared to the copy number of USP10. The signature reflects the level of SKP2 activity, stratifying BC patients into two groups with significantly different protein levels of SKP2 ubiquitination substrate p27 (t-test p < 0.01) and recapitulating the expression patterns of SKP2 between tumor and normal tissue (Spearman’s ρ = 0.39.) The signature is also highly associated with clinical outcome in luminal BC but not other subtypes, characterizing patients into two groups with significantly different overall survival times (log-rank p = 0.006). In addition, it is dramatically associated with tumor grade (Chi-squared p = 6.7 × 10−3), stage (Chi-squared p = 1.6 × 10−11), and the number of positive lymph nodes (negative binomial regression coefficient p = 2.0 × 10−3). Our study provides a rationale for targeting the SKP2 ubiquitination pathway in luminal BC and for further investigation of the use of ubiquitinase/deubiquitinase genes as prognosis and treatment biomarkers.