DJ-1, a Novel Androgen Receptor Binding Protein, Activates Receptor Signaling In Prostate Cancer and Correlates with the Development of Androgen-Independent Disease

Abstract

DJ-1, A NOVEL ANDROGEN RECEPTOR BINDING PROTEIN, ACTIVATES RECEPTOR SIGNALING IN PROSTATE CANCER AND CORRELATES WITH THE DEVELOPMENT OF ANDROGEN-INDEPENDENT DISEASE

Jennifer Erin Tillman

Dissertation completed under the direction of Dr. Susan Kasper, PhD This research projects focused on investigation of the role of DJ-1 in prostate cancer. In this dissertation, the mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer were investigated by analyzing androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial cells and established prostate cancer cell lines. We determined that flutamide treatment exhibited agonist activities in cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, an oncogene and positive regulator of AR. DJ-1 expression increased following flutamide treatment as a result of DJ-1 protein stabilization. To address the function of DJ-1 in prostate, we performed a yeast two-hybrid screen to identify novel DJ-1 binding proteins. The androgen receptor (AR) was identified as a putative DJ-1 binding protein, which was confirmed in the LAPC4 and LNCaP human prostate cancer cell lines. This is the first evidence that DJ-1 directly interacts with AR. We also demonstrate that modulation of DJ-1 expression regulates AR transcriptional activity. Importantly, both the subcellular localization of DJ-1 and the interaction with AR is regulated by androgens and anti-androgens. Additionally, we performed immunohistochemical staining on two human prostate cancer tissue arrays providing the first large scale expression analysis of DJ-1 in prostate. DJ-1 expression does not change with Gleason pattern, but increases after androgen deprivation therapy, indicating that it may be involved in the development of androgen independence. Taken together, we demonstrate that DJ-1 directly interacts with AR, and that this interaction is hormonally regulated. These data provide a novel mechanism for DJ-1 mediated regulation of AR in the progression of prostate cancer to androgen-independence.