USP7 Inhibitors Destabilize EBNA1 and Suppress Epstein-Barr Virus Tumorigenesis.

in Journal of medical virology by Christopher Chen, Kush Addepalli, Samantha S Soldan, Leonardo Josue Castro-Munoz, Sarah Preston-Alp, Rishi J Patel, Coltin J Albitz, Hsin-Yao Tang, Italo Tempera, Paul M Lieberman

TLDR

  • USP7 inhibitors reduce EBNA1 protein levels and inhibit EBV replication by disrupting USP7 association with EBNA1 and reducing viral episome copy number.
  • The study suggests that USP7 inhibitors may be a potential therapeutic strategy for treating EBV-related cancers
  • Further studies are needed to investigate the use of USP7 inhibitors in combination with other therapies to improve treatment outcomes

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human ɣ-herpesvirus implicated in various malignancies, including Burkitt's lymphoma and gastric carcinomas. In most EBV-associated cancers, the viral genome is maintained as an extrachromosomal episome by the EBV nuclear antigen-1 (EBNA1). EBNA1 is considered to be a highly stable protein that interacts with the ubiquitin-specific protease 7 (USP7). Here, we show that pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 reduce EBNA1 protein levels in a proteosome-dependent manner. Proteomic analysis revealed that USP7 inhibitor GNE6776 altered the EBNA1 protein interactome, including disrupting USP7 association with EBNA1. GNE6776 also inhibited EBNA1 binding to EBV oriP DNA and reduced viral episome copy number. Transcriptomic studies revealed that USP7 inhibition affected chromosome segregation and mitotic cell division pathways in EBVcells. Finally, we show that GNE6776 selectively inhibited EBVgastric and lymphoid cell proliferation in cell culture and slowed EBVtumor growth in mouse xenograft models. These findings suggest that USP7 inhibitors perturb EBNA1 stability and function and may be exploited to treat EBV latent infection and tumorigenesis.

Overview

  • The study investigates the role of ubiquitin-specific protease 7 (USP7) in Epstein-Barr virus (EBV) and its potential to treat EBV-related cancers.
  • EBV is a ubiquitous human herpesvirus that is implicated in various malignancies, including Burkitt's lymphoma and gastric carcinomas.
  • The study aims to determine whether pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 can reduce EBNA1 protein levels and inhibit EBV replication.

Comparative Analysis & Findings

  • Pharmacological inhibitors and siRNA targeting USP7 reduced EBNA1 protein levels in a proteosome-dependent manner.
  • Proteomic analysis revealed that the USP7 inhibitor GNE6776 altered the EBNA1 protein interactome, including disrupting USP7 association with EBNA1.
  • GNE6776 also inhibited EBNA1 binding to EBV oriP DNA and reduced viral episome copy number.

Implications and Future Directions

  • The study suggests that USP7 inhibitors may be exploited to treat EBV latent infection and tumorigenesis.
  • The findings imply that USP7 plays a crucial role in maintaining EBNA1 stability and function, which is necessary for EBV replication and tumorigenesis.
  • Future studies could investigate the use of USP7 inhibitors in combination with other therapies to improve treatment outcomes for EBV-related cancers.
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