TAF1, From a General Transcription Factor to Modulator of Androgen Receptor in Prostate Cancer

摘要

The androgen receptor (AR) is a ligand-activated transcription factor that is essential for development and progression of prostate cancer. Using the N-terminus of AR as bait in the repressed transactivator yeast two- hybrid system, TAF1 was identified. TAF1 interacts with several proteins to promote or suppress gene transcription. In the present study, using GST pull- down assay we confirmed that TAF1 binds to NTD of AR through the E1/E2 and HAT domains. We demonstrated by co-immunoprecipitation and ChIP assays that TAF1 and AR bind in the nucleus and associate with an androgen response elements at the proximal/enhancer promoter of the prostate specific antigen (PSA) gene when the AR is transcriptionally active. In addition, TAF1 was shown in human prostate cancer tissue microarrays to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. Furthermore, we found that TAF1 enhances AR transcriptional activity through its NTK and E1/E2 domains probably through ubiquitination of AR. In conclusion, our results indicate that increased TAF1 expression is associated with progression of human prostate cancers to the castration-resistant state. Since TAF1 is a coactivator of AR that binds and enhances AR transcriptional activity, its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens.