title: Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells.
abstract: Androgen receptor (AR) functions as a transcriptional factor for genes involved in proliferation and differentiation of normal and cancerous prostate cells. Coactivators that bind to AR are required for maximal androgen action. Here we report that increasing the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a prostate cancer cell line by as little as 1.8-fold enhances transcriptional activity of AR (but not the transcriptional activity of glucocorticoid receptor or estrogen receptor alpha) in a ligand-dependent manner and results in an increased expression of prostate-specific antigen. Small interference RNA-mediated knockdown of GAPDH significantly attenuated ligand-activated AR transactivation. Immunoprecipitation analysis revealed the presence of an endogenous protein complex containing GAPDH and AR in both the cytoplasm and nucleus. Addition of a nuclear localization signal (NLS) to GAPDH (GAPDH-NLS) completely abolished the ability of GAPDH to transactivate AR. Neither wild-type GAPDH nor GAPDH-NLS enhanced transcriptional activity of mutant AR (AR Delta C-Nuc) that is a constitutively active form of AR in the nucleus, even though GAPDH-NLS formed a complex with wild-type AR or AR Delta C-Nuc. AR transactivation was enhanced by a mutant GAPDH lacking dehydrogenase activity. GAPDH enhanced the transcriptional activity of AR(T875A) activated by an antagonist such as hydroxyflutamide or cyproterone acetate. These results indicate that GAPDH functions as a coactivator with high selectivity for AR and enhances AR transactivation independent of its glycolytic activity. Further, these data suggest that formation of a GAPDH.AR complex in the cytoplasm rather than nucleus is essential for GAPDH to enhance AR transactivation.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yasunaga
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Higashimura
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D008297:Male; D019913:Nuclear Localization Signals / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C410798:AR protein, human; D000728:Androgens; D019913:Nuclear Localization Signals; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases