Projekt 9

ANALYSIS OF RAI2 AND CTBP FUNCTION IN ANTI-ANDROGEN RESISTANCE AND GENOMIC INTEGRITY IN PROSTATE CANCER CELLS

Despite early detection and improved therapeutic options, prostate cancer (PCa) is still the second-leading cause for cancer related deaths of men in the western society. Major problem in PCa treatment is the development of androgen resistance during androgen depletion therapy, often leading to castration-resistant prostate cancer (CRPC). Aim of this project is to get a deeper insight into the molecular mechanisms underlying this process by analysis of the functional association between the RAI2 protein and C-terminal binding proteins (CtBPs).

The RAI2 protein has been initially identified at the ITB as a potential metastasis-suppressor gene associated with early occurring bone metastasis and poor prognosis in hormone-dependent breast cancer patients (Werner et al., 2015). CtBPs are transcriptional co-repressors overexpressed in many cancer types. Interestingly, the RAI2 protein can bind two CtBP tetramers via a non-consensus tandem motif. After binding, RAI2 induces CtBP polymerization and the formation of protein aggregates in the nuclei of cancer cells. This RAI2-induced polymerization can inhibit the repressor and thus the oncogenic activity of CtBPs.

By performing functional analysis of newly established PCa cell lines with genetically modified CtBP expression, we focus on the question how the interaction of RAI2 and CtBPs contributes to PCa progression. Additionally, it is aimed to decipher the transcriptional network of CtBPs in PCa by the combination of different genome wide approaches (ChIP-seq, RNA-seq, methylation assays) and to validate the findings in clinical samples.

In the end, our studies are intended to provide us with advanced knowledge about the molecular mechanisms of PCa development and progression, which could contribute to enhance therapeutic approaches for PCa patients.