title: Androgen receptor primes prostate cancer cells to apoptosis through down-regulation of basal p21 expression.
abstract: The androgen receptor (AR) for the male hormone androgen plays an important role in regulation of cell survival or death depending on the nature of cellular context and extracellular stimuli. The pro-survival function of AR is mediated mainly by transcriptional regulation of its target genes. By contrast, the pro-death function of AR can be transcription-dependent or -independent, although the underlying mechanism of the latter is incompletely understood. Here we report that, in androgen-independent prostate cancer cells, AR promotes UV-induced apoptosis through down-regulation of basal expression of p21 independently of its transcriptional activity. Down-regulation of basal p21 expression depends on AR N-terminal interacting protein PIRH2, an E3 ligase for proteasomal degradation of p53. Silencing of PIRH2 up-regulates p53, which in turn activates p21 transcription. Consistent with this, knockdown of PIRH2 suppresses UV-induced AR-dependent apoptosis. Our data suggest that AR primes androgen-independent prostate cancer cells to DNA damage-induced apoptosis through the PIRH2-p53-p21 axis.
authors.affiliation: Biology Division, Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL 60616, United States.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Lin
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Lu
authors.forename: John
authors.initials: J
authors.lastname: Kokontis
authors.forename: Jialing
authors.initials: J
authors.lastname: Xiang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: C410798:AR protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases