Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells.

Authors

Victoria J. Gennaro, Thomas Jefferson UniversityFollow
Timothy J. Stanek, Thomas Jefferson UniversityFollow
Amy R. Peck, Medical College of Wisconsin
Yunguang Sun, Medical College of Wisconsin
Feng Wang, Progenra, Inc.
Shuo Qie, Medical University of South Carolina
Karen E. Knudsen, Thomas Jefferson UniversityFollow
Hallgeir Rui, Medical College of Wisconsin
Tauseef Butt, Progenra, Inc.
J. Alan Diehl, Medical University of South Carolina
Steven B. McMahon, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-2-2018

Comments

This article is the author’s final published version in the Proceedings of the National Academy of Sciences of the United States of America, Volume 115, Issue 40, October 2018, Pages E9298-E9307.

The published version is available at https://doi.org/10.1073/pnas.1807704115. Copyright © Gennaro et al.

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.

Recommended Citation

Gennaro, Victoria J.; Stanek, Timothy J.; Peck, Amy R.; Sun, Yunguang; Wang, Feng; Qie, Shuo; Knudsen, Karen E.; Rui, Hallgeir; Butt, Tauseef; Diehl, J. Alan; and McMahon, Steven B., "Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells." (2018). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 160.
https://jdc.jefferson.edu/bmpfp/160

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

30224477

Language

English