title: Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor.
abstract: It has been noticed that crosstalk between androgen receptor (AR) and mammalian target of rapamycin (mTOR) signaling pathways plays a crucial role in the proliferation of prostate cancer cells. To clarify this mechanism, we focused on DEPTOR, a naturally occurring inhibitor of mTOR. The treatment of a human AR-positive prostate cancer cell line, LNCaP, with the AR-agonist dihydrotestosterone (DHT) repressed DEPTOR mRNA expression in a time-dependent manner. This repression was abrogated by treatment with the AR-antagonist bicalutamide. Knockdown of DEPTOR mRNA by siRNA resulted in the increased phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (S6K), a substrate of mTORC1, accompanied by the elevated expression of cyclin D1, a positive regulator of cell proliferation. Furthermore, the ChIP assay demonstrated that AR could bind to AR-responsible element-like region within the 4th intron of the DEPTOR gene. The amount of acetylated histone H3 (Lys9, Lys14) was reduced by the DHT treatment in this region. Taken together, these results propose that AR-dependent prostate cancer cell proliferation requires decreased DEPTOR transcription directly controlled by AR.
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kanno
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhao
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamashita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yanai
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Nemoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Inouye
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D011944:Receptors, Androgen / Q000378:metabolism / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D019938:Cyclin D1; C053541:bicalutamide; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1