Mechanisms and Impact of DNA Repair Dysfunction in Prostate Cancer

Prostate cancer (PCa) remains the second leading cause of cancer-related death in men in the United States. While organ confined disease can be successfully treated by radical prostatectomy or radiation therapy, disseminated disease is treated with androgen deprivation therapy (ADT), as PCa cells are exquisitely reliant on the androgen receptor (AR) for cell proliferation and survival. ADT is effective for 24 to 36 months, at which point AR is re-activated and the tumor recurs, leading to the lethal stage of disease, known as castration resistant prostate cancer (CRPC). Prostate cancer generally exhibits a low mutation burden, as compared to many other tumor types, yet alterations in the DNA damage response and repair (DDR) pathway remain recurrent in the transition from hormone therapy sensitive PCa (HSPC) to CRPC. Importantly, mutations in TP53 (mut-p53) represent the most frequent genetic mutation in CRPC, and these mutations cluster to the p53 DNA binding domain. The R273 residue of p53 is the most frequently altered with a selective enrichment of an R273C-p53 mutation compared to an R273H-p53 mutation in PCa. Importantly, mut-p53 can occur in a heterozygous and loss of heterozygosity (LOH) context. Both R273C-p53 and R273H-p53 expression induced similar transcriptional pathway enrichment in the p53-wt-null context. Conversely, R273C-p53 and R273H-p53 demonstrated differing transcriptional pathway enrichment profiles in the presence of p53-wt expression, indicating the importance of the context of mut-p53 expression. While mutations occur in DDR machinery in CRPC, alterations in ubiquitin modifiers that modulate the DDR are also apparent in PCa. Expression of the deubiquitinase USP22 increases as a function of PCa progression, and USP22 is altered in both primary and advanced PCa. USP22 alterations also were found to be associated with decreased disease-free survival and USP22 expression positively correlated with expression of the oncogenes MYC or AR. A novel GEMM of tumor-associated USP22 upregulation demonstrated increased proliferative phenotypes, and subsequent identification of the USP22-sensitive transcriptome and ubiquitylome in PCa models, demonstrated enrichment of cell cycle and DNA repair-related pathways. As a result, the nucleotide excision repair protein XPC was validated as a target of USP22 de-polyubiquitylation to promote the response to genotoxic insult. Thus, the USP22-mediated response to genotoxic insult relies on regulation of XPC activity. In sum, modulation of DDR allows cancer cell survival and PCa progression