Novel Mechanisms of Androgen Receptor Signaling in Prostate Cancer



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Androgens regulate the physiological development of the prostate and the pathology of prostate cancer. Androgen-receptor (AR)-mediated transcriptional activity is a driver of prostate cancer (PCa) progression. AR-induced transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in AR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of specific subsets AR-regulated genes. Despite continual improvement in design and enhanced efficacy, PCa cells eventually become resistant to AR-antagonists and anti-androgen treatment. Therefore, in this dissertation, we have proposed and identified two novel mechanisms of harnessing AR-mediated gene transcription in PCa. First, we show that a stretch of proline residues located within the N-terminus of AR is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer cells. Using T7 phage display, we identified a novel AR-interacting protein, SH3YL1, whose interaction with the receptor is dependent upon this polyproline domain. As with mutations within the AR polyproline domain, knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for the induction of a subset of AR-modulated genes. Notable was the observation that ubinuclein1 (UBN1), a key member of a histone H3.3 chaperone complex, was a transcriptional target of the AR/SH3YL1 complex, correlated with aggressive prostate cancer in patients, and was necessary for the maximal androgen-mediated proliferation and migration of prostate cancer cells. Collectively, these data highlight the importance of an amino-terminal activation domain, its associated coregulator, and downstream transcriptional targets in regulating cellular processes of pathological importance in prostate cancer. In the second approach of this dissertation, we studied the downstream AR targets that regulate autophagy. We have determined that 1) androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells, 2) functional autophagy was clinically detected in metastatic, castration-resistant cancers but not treatment-naïve, localized tumors and 3) autophagy is required for prostate cancer progression in preclinical animal models. Inhibition of autophagy using molecular inhibitors significantly abrogated androgen-induced prostate cancer cell/tumor growth. Autophagy and subsequent cell growth is potentiated by androgen-mediated increases in the expression and activity of several core autophagy genes, including ULK1, ULK2, AT4B, ATG4D, and TFEB. We identify these five genes as direct targets of the androgen receptor (AR) in prostate cancer. Moreover, expression of these five genes is essential for maximal androgen-mediated autophagy and cell proliferation. These findings demonstrate a role for increased autophagy in prostate cancer and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics.



Androgen receptor, Prostate cancer, SH3YL1, Ubinuclein1 (UBN1), Autophagy, Polyproline


Portions of this document appear in: Blessing, Alicia M., Sathya Ganesan, Kimal Rajapakshe, Ying Ying Sung, Lakshmi Reddy Bollu, Yan Shi, Edwin Cheung et al. "Identification of a novel coregulator, SH3YL1, that interacts with the androgen receptor N-terminus." Molecular endocrinology 29, no. 10 (2015): 1426-1439.