TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer

Ken Ichi Takayama, Kuniko Horie-Inoue, Takashi Suzuki, Tomohiko Urano, Kazuhiro Ikeda, Tetsuya Fujimura, Satoru Takahashi, Yukio Homma, Yasuyoshi Ouchi, Satoshi Inoue

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.Weidentified 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.

Original languageEnglish
Pages (from-to)748-761
Number of pages14
JournalMolecular Endocrinology
Volume26
Issue number5
DOIs
Publication statusPublished - 2012 May

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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