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Epigenetic modifications of androgen receptor signaling in castration resistant prostate cancer (CRPC)

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Introduction: Prostate cancer is one of the most common forms of cancer in Turkish and European men. For those patients with late-stage prostate cancer, androgen depletion therapy is current standard treatment. While initially successful, almost all patients eventually develop resistance against this treatment. Once the cancer reaches this advanced, progressive form, it is termed castration resistant prostate cancer (CRPC). Whereas the progression mechanisms of CRPC are poorly understood, it has been shown that in CRPC patients, the androgen receptor (AR) is still active despite undetectable androgen levels. Since AR signaling is important in the progression and growth of prostate cancer, understanding how AR mediated signaling occurs in CRPC is critical to more efficient treatment of this recurrent disease. Material and Methods: There are several possible causes for this conversion from androgen-sensitive to androgen-independent prostate cancer. Previous work has demonstrated that epigenetic modifiers such as EZH2 and LSD1 can mediate the sensitization of androgen receptor in CRPC. However, only a small subset of epigenetic modifiers has been characterized. To better understand the role of histone modification on CRPC, we conducted a large scale shRNA screen of epigenetic modifying enzymes to identify those genes that prevent androgen-independent growth. Results and Discussion: From this screen several hit genes have been found that cause a reversion of androgen-independent to androgen-dependent prostate cancer. The shRNA knock-down of these hit genes was confirmed by western blot and qRT-PCR. We are currently characterizing how these epigenetic modifiers affect androgen-receptor mediated signalling. Conclusion: These results will offer new insight into the role of epigenetic modifiers in nuclear receptor signalling.

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Elsevier Sci Ltd

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oncology

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European Journal of Cancer

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10.1016/S0959-8049(14)50369-3

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