title: TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer.
abstract: Despite the existence of effective antiandrogen therapy for prostate cancer, the disease often progresses to castration-resistant states. Elucidation of the molecular mechanisms underlying the resistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathways is a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy, we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. We discovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coil protein 2 (TACC2), is a novel androgen-regulated gene. We identified a functional AR-binding site (ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, in which activated hallmarks of histone modification were observed. Androgen-dependent TACC2 induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitor bicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstrated that TACC2 is highly expressed and contributes to hormone-refractory proliferation, as small interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression. By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. In vivo tumor formation study of prostate cancer in castrated immunocompromised mice revealed that TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstrated by a correlation between high TACC2 expression and poor survival rates. Taken together with the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer that the molecule is a potential therapeutic target in CRPC as well as hormone-sensitive prostate cancer.
authors.affiliation: Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Kuniko
authors.initials: K
authors.lastname: Horie-Inoue
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000728:Androgens; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D011994:Recombinant Proteins; C410333:TACC2 protein, human; D025521:Tumor Suppressor Proteins