Ser815 Phosphorylation stabilizes the androgen receptor homodimer and stimulates ER-stress induced cell death

Androgen receptor, which regulates diverse biological processes for cell fate decisions, forms a homodimer in the cytoplasm and is monomerized by activation for nuclear translocation. Ser815 phosphorylated AR is expressed in mature prostates, with levels decreased by castration in mice or prostate cancer progression in humans. Here, we have examined the functional and biological roles of phosphorylation. AR phosphorylation at Ser815 stabilized homodimer formation in the cytoplasm, interrupting DHT-response nuclear translocation. cDNA microarray studies in castrated mouse prostates implied castration attenuates ER stress responses, suggesting AR phosphorylation acts on ER stress responses. In addition, AR Ser815Asp phospho-mimetic mutant expression augmented ER stress-induced death in PC-3 cells. These results suggested that phosphorylation at AR Ser815 modulates AR functions for maintaining the prostate. •Androgen receptor phosphorylated at Ser815 (P-AR) forms a homodimer in cytoplasm.•P-AR disturbs ligand-induced monomerization, inhibiting nuclear translocation.•P-AR induces endoplasmic reticulum stress-induced cell death.