Prostate cancer (PCa) is the second leading cause of cancer-related death for men in the United States. While organ-confined disease is manageable, advanced and disseminated PCa currently has no durable treatment options. Thus, understanding the causes and consequences of the transition from early stage to late stage castrate-resistant PCa (CRPC) are critical. While this transition has a requisite for androgen receptor (AR) activity, the mechanisms by which AR and other oncogenes are functionally increased, even after initial treatment with androgen deprivation therapy (ADT) have not been completely characterized. USP22, a known deubiquitinase associated with the SAGA transcriptional activation complex, was originally designated in a ?death from cancer? gene signature. Importantly, USP22 is significantly upregulated in PCa patients with late-stage disease, and specifically indicates for poor outcome in PCa patients. Moreover, tumor-associated USP22 increases AR levels and activity as well as the c-MYC function, partially defining the mechanism by which tumor-associated USP22 drives PCa progression. Thus, while certain consequences of tumor-associated USP22 expression have been elucidated, the remaining downstream effects have not been thoroughly characterized. In this proposal, I will delineate the manner by which USP22 drives PCa development and progression. Specifically, I will describe the biochemical events controlled by USP22 that confer proliferation and survival on PCa cells, and furthermore I will define the role of tumor-associated USP22 on tumor development and therapeutic bypass in vivo. Moreover, I will expand on my ambition to continue studying transcriptional deregulation in cancer once I complete my predoctoral research.
Prostate Cancer (PCa) exists as a leading cause of male cancer-related death in the United States, and studies from our lab have shown that upregulation of the deubiquitinase USP22 is capable of driving PCa progression via the AR/MYC axes. Importantly, USP22, a component of the SAGA transcriptional activation complex and a member of an established ?death from cancer? gene signature, is overexpressed in late-stage PCa human clinical samples, acting as an indicator of poor outcome in PCa patients. Here I intend to further characterize the biochemical means with which USP22 drives PCa progression, and demonstrate the effects of tumor-associated USP22 on therapeutic bypass.
