USP11 promotes growth and metastasis of colorectal cancer via PPP1CA-mediated activation of ERK/MAPK signaling pathway

BACKGROUND: USP11 is an ubiquitin-specific protease that plays an important role in tumor progression via different mechanisms. However, the expression and prognostic significance of USP11 in colorectal cancer (CRC) remain unknown. METHODS: Bioinformatics analyses, qRT-PCR, western blotting, and immunohistochemistry were applied for investigating USP11 expression in CRC tissues. Kaplan–Meier analysis with log-rank test was used for survival analyses. LC–MS/MS was performed for identifying potential protein interactions with USP11. In vitro and in vivo assays were used for exploring the function of USP11 during the progression of CRC. FINDINGS: USP11 was overexpressed in CRC tissues and functioned as an oncogene. Overexpression or knockdown of USP11 promoted or inhibited, respectively, the growth and metastasis of CRC cells in vitro and in vivo. Mechanically, USP11 stabilized PPP1CA by deubiquitinating and protecting it from proteasome-mediated degradation. Moreover, the USP11/PPP1CA complex promoted CRC progression by activating the ERK/MAPK signaling pathway. INTERPRETATION: USP11 promoted tumor growth and metastasis in CRC via the ERK/MAPK pathway by stabilizing PPP1CA, suggesting USP11 is a potential prognostic marker. FUND: This work was supported by National Natural Science Foundation of China (NSFC81530044, NSFC81220108021, NSFC81802343), Technology Major Project of China Grants 2017ZX10203206, Shanghai Sailing Program (19YF1409600) and The project of Shanghai Jiaotong University (YG2017QN30).