Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27)

Abstract

The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.

Endocrine Disruptors and Prostate Cancer

“…Cav-1 enhances AR-transcriptional activity after the androgen binds to the AR as it may increase nuclear translocation and phosphorylation of the AR itself. On the other hand, a downregulation of Cav-1 decreases AR membrane localization [44,45]. Overall, the effects elicited by androgens are obtained by different signal transduction pathways (e.g., nuclear and extra-nuclear), whose activation depends on the cellular context of the target cell, the AR intracellular localization (e.g., membrane-bound, cytosolic, nuclear), and the ligand itself (e.g., T vs. DHT).…”

“…The sequence comparison between AR and ERs shows a similar sequence for the palmitoylation, a post-translational modification, present in both types of sex steroid receptors. The palmitoylation of a conserved motif in the ligand-binding domain is critical for the membrane localization of both ERs and AR [18,44]. The localization at the level of the plasma membrane of the AR and its interaction with caveolin-1 (Cav-1), a major component of the caveolae membrane structure, is due to palmitoylation [44,45].…”

“…The palmitoylation of a conserved motif in the ligand-binding domain is critical for the membrane localization of both ERs and AR [18,44]. The localization at the level of the plasma membrane of the AR and its interaction with caveolin-1 (Cav-1), a major component of the caveolae membrane structure, is due to palmitoylation [44,45]. Cav-1 enhances AR-transcriptional activity after the androgen binds to the AR as it may increase nuclear translocation and phosphorylation of the AR itself.…”

Stromal Fibroblasts Counteract the Caveolin-1-Dependent Radiation Response of LNCaP Prostate Carcinoma Cells

“…Mechanistically androgen receptor binding was achieved by CAV1 palmitoylation of the cysteine residues (41). Membrane-association in turn was shown to potentiate androgen receptor transcriptional activities by activating HSP27 further indicating that disruption of androgen receptor membrane translocation could represent a potential strategy for improving PCa therapy (42). Moreover, the metastatic spread as well as progression to castration-resistant PCa was already linked to increasing expression levels of HSP27 (43).…”

The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction

“…Hsp27 was also found to regulate lung fibroblast differentiation in response to TGF-b via activation of Smad3 and ERK-MAPK (Wang et al, 2017). Other receptor systems have also been implicated in Hsp27 signaling: These include the membrane-associated androgen receptor (Li et al, 2018) and endothelin-1 stimulation (Fujita et al, 2018). Hsp27 has further been implicated in different physiologic processes downstream of these receptors.…”