USP13 deubiquitinates and stabilizes cyclin D1 to promote gastric cancer cell cycle progression and cell proliferation

Abstract

AbstractThe reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the occurrence and development of tumors. In this study, we investigated the gastric cancer (GC) data from the TCGA and GEO databases and found that ubiquitin-specific protease USP13 was significantly up-regulated in GC samples. The higher expression of USP13 was associated with the worse prognosis and shorter overall survival (OS) of GC patients. Enforced expression of USP13 in GC cells promoted the cell cycle progression and cell proliferation in an enzymatically dependent manner. Conversely, suppression of USP13 led to GC cell cycle arrest in G1 phase and the inhibition of cell proliferation. Nude mouse experiments indicated that depletion of USP13 in GC cells dramatically suppressed tumor growth in vivo. Mechanistically, USP13 physically bound to the N-terminal domain of cyclin D1 and removed its K48- but not K63-linked polyubiquitination chain, thereby stabilizing and increasing cyclin D1. Furthermore, re-expression of cyclin D1 partially reversed the cell cycle arrest and cell proliferation inhibition induced by USP13 depletion in GC cells. Additionally, USP13 protein abundance was positively correlated with the protein level of cyclin D1 in human GC tissues. Taken together, our data demonstrate that USP13 deubiquitinates and stabilizes cyclin D1, thereby promoting cell cycle progression and cell proliferation in GC. These findings suggest that USP13 might be a promising therapeutic target for the treatment of GC.