Characterizing the Role of Epigenetic Regulator USP22 in Human Cancer

Timothy J Stanek, Thomas Jefferson University

Abstract

Overexpression of the deubiquitylase USP22 drives aggressive cancer phenotypes like metastasis and therapy resistance. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the SAGA transcriptional cofactor complex. We report here a non-transcriptional role for USP22 via a direct effect on the core cell cycle machinery, i.e. 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. Functionally, we demonstrate that control of CCND1 largely explains the 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. SAGA is a modular cofactor complex that is essential for eukaryotic transcription. SAGA’s complement of ~20 proteins exist within four structurally and functionally distinct modules, two of which are catalytic. Within the KAT module, GCN5 acetylates histone tails, leading to increased chromatin accessibility and bromodomain protein recruitment. The DUB module contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II S2 phosphorylation and subsequent transcriptional elongation. We report here that metazoan SAGA, and USP22 specifically, are required at a more proximal stage in activator-driven transcription, i.e. pre-initiation complex (PIC) assembly. A combination of genome-wide and proteomic analyses revealed that H2B deubiquitylation is not linked to USP22-dependent transcription. Instead, USP22 controls Mediator tail subunit ubiquitylation. Mechanistically, USP22 controls loading of Mediator tail and GTFs onto promoters, with Mediator core recruitment being USP22-independent. These findings place human SAGA function at the earliest steps in activator-driven transcription.

Subject Area

Molecular biology

Recommended Citation

Stanek, Timothy J, "Characterizing the Role of Epigenetic Regulator USP22 in Human Cancer" (2019). ETD Collection for Thomas Jefferson University. AAI13811154.
https://jdc.jefferson.edu/dissertations/AAI13811154

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