USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.

Authors

• Randy S Schrecengost
• Jeffry L Dean
• Jonathan F Goodwin
• Matthew J Schiewer
• Mark W Urban
• Timothy J Stanek
• Robyn T Sussman
• Jessica L Hicks
• Ruth C Birbe
• Rossitza A Draganova-Tacheva
• Tapio Visakorpi
• Angelo M DeMarzo
• Steven B McMahon
• Karen E Knudsen

Publication/Presentation Date

1-1-2014

Abstract

Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.

Volume

74

Issue

1

First Page

272

Last Page

286

ISSN

1538-7445

Published In/Presented At

Schrecengost, R. S., Dean, J. L., Goodwin, J. F., Schiewer, M. J., Urban, M. W., Stanek, T. J., Sussman, R. T., Hicks, J. L., Birbe, R. C., Draganova-Tacheva, R. A., Visakorpi, T., DeMarzo, A. M., McMahon, S. B., & Knudsen, K. E. (2014). USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer research, 74(1), 272–286. https://doi.org/10.1158/0008-5472.CAN-13-1954

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

24197134

Department(s)

Administration and Leadership

Document Type

Article