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Androgen-independent/castration-resistant progression of is a main obstacle to improve survival of advanced prostate cancer. Alternative activation of the androgen receptor (AR) in the presence of castration level of androgens through AR-interacting coregulators is implicated as one of the major mechanisms that facilitates androgen independent growth and survival of hormone-refractory prostate cancer. We have recently identified two RNA splicing factors, PSF (PTB-associated splicing factors) and its heterodimer partner p54nrb, that function as novel ligand-independent corepressors of the AR in several cell and promoter contexts. Expression distributions of PSF and p54nrb overlap with that of the AR in prostate cancer biopsies. Chromatin immunoprecipitation (CHIP) and re-CHIP assays showed that PSF formed protein complex with the AR on the androgen response elements (ARE) within the PSA promoter. Using electrophoresis mobility shift assays, we showed that PSF but not p54nrb interferes with AR binding to a consensus ARE oligo. Both PSF and p54nrb interact directly with the mSin3A (components of the mSin3A/HDAC complex that inhibits gene transcription) and overexpression of PSF and p54nrb enhanced the recruitments of mSin3A and HDAC1 to the AREs in the PSA gene. Our results demonstrated that PSF and p54nrb are novel corepressors of AR and suggest that PSF and p54nrb may play key roles in PCa progression to the androgen independent state and serve as therapeutic targets for patients with castration-resistant tumor growth.
 Key words: prostate cancer, androgen independence, androgen receptor, transcription
 corepressor, RNA splicing factor

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA