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.
[Show abstract][Hide abstract] ABSTRACT: The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.
International Journal of Urology 04/2013; 20(8). DOI:10.1111/iju.12146 · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fine-tuned regulation of the centrosome/microtubule dynamics during mitosis is essential for faithful cell division. Thus, it is not surprising that deregulations in this dynamic network can contribute to genomic instability and tumorigenesis. Indeed, centrosome loss or amplification, spindle multipolarity and aneuploidy are often found in a majority of human malignancies, suggesting that defects in centrosome and associated microtubules may be directly or indirectly linked to cancer. Therefore, future research to identify and characterize genes required for the normal centrosome function and microtubule dynamics may help us gain insight into the complexity of cancer, and further provide new avenues for prognostic, diagnostics and therapeutic interventions. Members of the transforming acidic coiled-coil proteins (TACCs) family are emerging as important players of centrosome and microtubule-associated functions. Growing evidence indicates that TACCs are involved in the progression of certain solid tumors. Here, we will discuss our current understanding of the biological function of TACCs, their relevance to human cancer and possible implications for cancer management.
Cancer letters 04/2013; 336(1). DOI:10.1016/j.canlet.2013.04.022 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.
The EMBO Journal 05/2013; 32(12). DOI:10.1038/emboj.2013.99 · 10.43 Impact Factor
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