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Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells. Proc Natl Acad Sci U S A 2018 10 02;115(40):E9298-E9307

Date

09/19/2018

Pubmed ID

30224477

Pubmed Central ID

PMC6176615

DOI

10.1073/pnas.1807704115

Scopus ID

2-s2.0-85054360749   28 Citations

Abstract

Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the core cell cycle machinery: that is, the deubiquitylation of the G1 cyclin D1 (CCND1). Deubiquitylation by USP22 protects CCND1 from proteasome-mediated degradation and occurs separately from the canonical phosphorylation/ubiquitylation mechanism previously shown to regulate CCND1 stability. We demonstrate that control of CCND1 is a key mechanism by which USP22 mediates its known role in cell cycle progression. Finally, USP22 and CCND1 levels correlate in patient lung and colorectal cancer samples and our preclinical studies indicate that targeting USP22 in combination with CDK inhibitors may offer an approach for treating cancer patients whose tumors exhibit elevated CCND1.

Author List

Gennaro VJ, Stanek TJ, Peck AR, Sun Y, Wang F, Qie S, Knudsen KE, Rui H, Butt T, Diehl JA, McMahon SB

Authors

Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Colorectal Neoplasms
Cyclin D1
Epigenesis, Genetic
G1 Phase
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
MCF-7 Cells
Protein Stability
Proteolysis
Thiolester Hydrolases
Ubiquitination
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a