Characterisation of the role of dual-specific MAP kinase phosphatases in androgen receptor action in prostate cancer development
Final Report Abstract
DUSP project: Mitogen-activated protein (MAP) kinases influence prostate cancer growth and progression by relaying information from extracellular signals to intracellular effectors, thereby impinging on cellular processes such as cell proliferation, migration and apoptosis. Their action can be controlled by phosphatases, such as the dual-specific phosphatases (DUSPs). Regulation of DUSP expression by androgens or antiandrogens could therefore have positive or negative actions on the growth of prostate cancer cells. In my study, a number of DUSPs could be identified that were responsive to androgens in prostate cancer cells and were also up-regulated in clinical patient samples. However other DUSPs displayed the opposite effect, where an increase in their expression correlated with better prognosis. A next objective would now be to knock-down the expression of the DUSPs that show changes in expression levels upon androgen treatment, in order to determine their impact on AR phosphorylation and gene regulation at different stages of prostate tumour development. This would provide valuable information on which DUSP to target pharmacologically in the future treatment of prostate cancer. H1 project: Previous reports as well as our preliminary data show that removal of linker histone H1 is a prerequisite for the full activation of AR-regulated target genes in prostate cancer cells. This process seems to be dependent on the activity of CDK2, which phosphorylates H1, and thereby loosens the interaction of the linker histone with DNA in chromatin. The goal of the proposed research project is to understand the mechanism in which H1 regulates AR-mediated gene expression, and how this regulation changes during cancer therapy and hormone resistance. I will particularly focus on differences between the H1 subtypes, which I expect to play distinct functional roles in the regulation of these processes. My hypothesis is that H1 dissociation is required for AR-mediated gene expression in prostate cancer and that H1 may act as a general transcriptional repressors in the hormone-refractory stage of this disease.
