Abstract
The elevated level of CCNB1 indicates more aggressive cancer and poor prognosis. However, the factors that cause CCNB1 upregulation remain enigmatic. Herein, we identify USP22 as a CCNB1 interactor and discover that both USP22 and CCNB1 are dramatically elevated with a strong positive correlation in colon cancer tissues. USP22 stabilizes CCNB1 by antagonizing proteasome-mediated degradation in a cell cycle-specific manner. Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1. The ubiquitin ligase anaphase-promoting complex (APC/C) targets USP22 for degradation by using the substrate adapter CDC20 during cell exit from M phase, presumably allowing CCNB1 degradation. Finally, we discover that USP22 knockdown leads to slower cell growth and reduced tumor size. Our study demonstrates that USP22 is a CCNB1 deubiquitinase, suggesting that targeting USP22 might be an effective approach to treat cancers with elevated CCNB1 expression.
Highlights
Colorectal cancer is the second leading cancer killer in the United States [1]
Together with the fact that cyclin-dependent kinase 1 (CDK1) and CDK3 were previously reported as cyclin B1 (CCNB1) interactors [29], these results indicate that our proteomic approach yielded highly specific and reliable
Our study demonstrates that Ubiquitin-specific protease 22 (USP22) is a CCNB1 deubiquitinase and overexpression of both proteins may be correlated with colorectal tumorigenesis
Summary
Colorectal cancer is the second leading cancer killer in the United States [1]. Despite successful surgical removal of colorectal tumors, a significant fraction of patients show a recurrence of the disease and metastasis. 11 genes have been identified as having death-from-cancer signatures displaying stem cell-like gene expression profiles in diverse solid tumors characterized by high malignancy and metastatic dissemination [2, 3]. Recent studies demonstrated that USP22 is a bona fide component of the deubiquitinating module of the mammalian SAGA (Spt-Ada-Gcn5-Acetyltransferase) complex [16,17,18] and is involved in transcriptional regulation, cell cycle progression, protein degradation and embryonic stem cell differentiation [19,20,21,22,23,24,25]. USP22 is highly expressed in many types of human cancers, including colon cancer [26]; the physiological functions of USP22 and its role in tumorigenesis, as well as the underlying molecular mechanisms resulting in both normal and abnormal cell cycle regulation, are largely unknown. How USP22 regulates cell cycle progression and how USP22 is regulated remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
