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Takayama K Horie-Inoue K Suzuki T Urano T Ikeda K Fujimura T Takahashi S Homma Y Ouchi Y Inoue S 《Molecular endocrinology (Baltimore, Md.)》2012,26(5):748-761
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. 相似文献
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Use of chromatin immunoprecipitation to clone novel E2F target promoters 总被引:20,自引:0,他引:20
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Weinmann AS Bartley SM Zhang T Zhang MQ Farnham PJ 《Molecular and cellular biology》2001,21(20):6820-6832
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Rivera-Gonzalez GC Droop AP Rippon HJ Tiemann K Pellacani D Georgopoulos LJ Maitland NJ 《Nucleic acids research》2012,40(11):4825-4840