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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.
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; McMahon, Steven B.
Afiliação
  • Gennaro VJ; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
  • Stanek TJ; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
  • Peck AR; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226.
  • Sun Y; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226.
  • Wang F; Progenra, Inc., Malvern, PA 19355.
  • Qie S; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
  • Knudsen KE; Department of Cancer Biology, Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
  • Rui H; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226.
  • Butt T; Progenra, Inc., Malvern, PA 19355.
  • Diehl JA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
  • McMahon SB; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107; steven.mcmahon@jefferson.edu.
Proc Natl Acad Sci U S A ; 115(40): E9298-E9307, 2018 10 02.
Article em En | MEDLINE | ID: mdl-30224477
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.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 / 2_ODS3 Base de dados: MEDLINE Assunto principal: Tioléster Hidrolases / Neoplasias Colorretais / Regulação Neoplásica da Expressão Gênica / Fase G1 / Ciclina D1 / Epigênese Genética / Ubiquitinação / Proteólise / Neoplasias Pulmonares Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 / 2_ODS3 Base de dados: MEDLINE Assunto principal: Tioléster Hidrolases / Neoplasias Colorretais / Regulação Neoplásica da Expressão Gênica / Fase G1 / Ciclina D1 / Epigênese Genética / Ubiquitinação / Proteólise / Neoplasias Pulmonares Limite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2018 Tipo de documento: Article