Determining the Effect of Targeting Androgen Receptor Acetylation in Prostate Cancer
Date of Award
Master of Science (MS)
Heather Montie, PhD
Ruth Borghaei, PhD
Cathy Hatcher, PhD
Marcus Bell, PhD
Prostate cancer (PCa) is the most common malignancy in American males. If diagnosed in early stages, prognosis following surgery and radiation is good. Aggressive forms of prostate cancer are treated with hormone therapies targeting the androgen receptor (AR) by limiting AR function antagonistically. However, there is almost always a decrease in the cancer’s dependency on androgens, rendering the AR antagonism useless, and this ‘castrate-resistant’ form of the disease is fatal. Due to the lack of a durable therapy for this aggressive form of prostate cancer (castration-resistant), it is imperative that new therapeutic strategies be identified. Using a castrate-resistant prostate cancer cell line (C4-2), our lab previously discovered that genetic inhibition of AR acetylation is an efficacious cellular treatment strategy, as it reduced cell proliferation and induced cell death. Due to these promising results, we hypothesized that targeting AR acetylation may be a means to enhance the function of AR antagonism, in inhibiting castrate-resistant prostate cancer viability. AR lysines 630/632/633 are deacetylated by SIRT1, and are acetylated by Tip60. We have optimized a method to measure AR acetylation in C4-2 cells and found that reducing AR acetylation with the SIRT1 activator, SRT1720, and Tip60 inhibitor, NU9506, inhibit castrate-resistant prostate cancer proliferation and induce cell death of castrate-resistant prostate cancer cells. Utilizing the recently approved second-generation AR antagonist, enzalutamide, we have found that neither SRT1720 nor NU9506 induced a synergistic effect with enzalutamide, and therefore would likely not prove to be of benefit over AR antagonism as a first line treatment of castrate-resistant disease. Overall, these studies have identified AR acetylation as a viable target for therapeutic development for the treatment of the most aggressive form of prostate cancer, castrate-resistant disease. Continued studies will inform iv as to where in the course of disease the treatment of targeting AR acetylation is most promising.
Nolte, Victoria, "Determining the Effect of Targeting Androgen Receptor Acetylation in Prostate Cancer" (2016). PCOM Biomedical Studies Student Scholarship. 134.