USP22 Function in Advanced Prostate Cancer

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 DESCRIPTION (provided by applicant): 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.