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.

• Authors: Jianzhuo Li, Xueqi Fu, Subing Cao, Jing Li, Shu Xing, Dongying Li, Yan Dong, Derrick Cardin, Hee-Won Park, Franck Mauvais-Jarvis, Haitao Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 33 Pg. 12719-12729 (08 17 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29934310 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AR protein, human
• HSP27 Heat-Shock Proteins
• HSPB1 protein, human
• Heat-Shock Proteins
• KIF5B protein, human
• Molecular Chaperones
• Receptors, Androgen
• Kinesins

Topics

• Cell Membrane (metabolism)
• Gene Expression Regulation, Neoplastic
• HSP27 Heat-Shock Proteins (genetics, metabolism)
• Heat-Shock Proteins
• Humans
• Kinesins (genetics, metabolism)
• Male
• Microtubules (metabolism)
• Molecular Chaperones
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Transport
• Receptors, Androgen (genetics, metabolism)
• Transcription, Genetic
• Tumor Cells, Cultured