Prostatic adenocarcinoma (PCa) is resistant to chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR), for growth, survival, and progression. As such, AR is the first line therapeutic target for all patient with disseminated disease. AR-directed therapies entail the use of androgen deprivation therapy (ADT), used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed castration-resistant prostate cancer (CRPC) is the incurable phase. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is inappropriately restored AR activity. Consonantly, preclinical modeling of AR upregulation showed that this event alone is sufficient to drive progression to CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, collaborative efforts between the Knudsen and McMahon labs unexpectedly identified deregulation of the SAGA complex member USP22, a known deubiquitylase, as a master regulator of AR levels and output that is sufficient to induce CRPC formation. Moreover, USP22-dependent SAGA activity proved requisite for c- Myc function in prostate cancer, suggesting that USP22 activity is critical for the two major oncogenic pathways that drive prostate cancer progression. Our collective findings have potentially dramatic clinical implications, and strongly support the hypothesis that deregulation of USP22 plays a major role in the transition to CRPC via regulation of the AR/Myc axis, and that targeting the enzymatic function of USP22 can be developed as a novel means of therapeutic intervention. The novel aims herein will illuminate the means by which USP22 modulates the two major pathways that govern prostate cancer development and progression, delineate the mechanisms through which USP22 promotes lethal tumor phenotypes, and comprehensively assess the in vivo and ex vivo impact of USP22 on tumor development and progression. On balance, the studies described will challenge the transformative concept that underpins aggressive prostate cancer phenotypes that can be targeted for therapeutic benefit.

Public Health Relevance

There is a significant need to understand the mechanisms that lead to prostate cancer growth and progression. Our data strongly suggest that USP22 plays a major role in the transition to CRPC via regulation of the AR/Myc axis, and that targeting the enzymatic function of USP22 can be developed as a novel means of therapeutic intervention The studies here will challenge this concept, provide molecular insight into the cellular and clinical consequence of USP22 activity, and have the potential for rapidly translatable outcomes to improve prostate cancer management.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA182569-03
Application #
9294005
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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