Olli A. Jänne

High androgen receptor (AR) level in primary prostate tumor predicts poor prognosis, but mechanisms that regulate AR function in prostate cancer are still elusive. We address AR signaling and transcription programs in prostate cancer cells and mouse tissues by using genome-wide approaches. In particular, we characterize the importance of other DNA-binding transcription factors (e.g., members of the FoxA family) for localization of AR-binding events on chromatin, androgen-dependent transcription programs, and determination of the specificity of receptor binding. In addition, we address genome-wide cross-talk between AR and other nuclear receptors, such as the glucocorticoid and vitamin D receptors. The results are anticipated to offer new opportunities for therapeutic intervention in prostate cancer. Another line of research deals with the importance of protein SUMOylation in metabolism and inflammation. SUMOylation is a dynamic process involving the covalent attachment of SUMO to target proteins, such as nuclear receptors.

We described recently a new paradigm for the forkhead protein FoxA1 action in AR pathway. Besides being a pioneer factor in AR signaling, FoxA1 has other important functions as well; its depletion elicits extensive redistribution of AR-binding sites (ARBs) on prostate cancer cell chromatin that is commensurate with changes in androgen-dependent gene expression signature. We identified three classes of ARBs and androgen-responsive genes; (i) independent of FoxA1, (ii) require FoxA1, and (iii) unmasked by FoxA1 depletion. FoxA1 depletion also reprograms glucocorticoid receptor binding and glucocorticoid-dependent signaling. High FoxA1 level in primary prostate cancers is associated with poor disease prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicts good disease outcome.

Our ongoing work addresses the following topics: (i) tissue- and cell-specific AR pathways; (ii) cross-talk of AR with other nuclear receptors in prostate cancer; and (iii) protein SUMOylation in fat cell biology.