Role of histone demethylase KDM5C in metastatic prostate cancer

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Cancer metastasis is devastating and clinically challenging. For metastasis, cancer cells acquire increased migratory and invasive abilities, which are in principle subject to epigenetic control. In our previous study, we reported that the histone demethylase KDM5C (lysine demethylase 5C, also called JARID1C or SMCX) is over-expressed in prostate cancer and that KDM5C is a prognostic marker for prostate-specific antigen-relapse following radical prostatectomy. Here, we show that KDM5C is highly up-regulated in metastatic prostate cancer and that down-regulation of KDM5C leads to decreased migration and invasion of prostate cancer cells. In the proposed project, we aim to expand the knowledge about the underlying molecular mechanism and the impact of the histone demethylase KDM5C in metastatic prostate cancer. Firstly, we will examine whether KDM5C influences prostate cancer cells by performing RNA-Seq of KDM5C-depleted and/or KDM5C over-expressing cells in comparison to control cells. By this we will determine the signaling pathway(s) through which KDM5C may affect tumor cell progression. Secondly, we want to determine if KDM5C occupies target genes and demethylates H3K4me3/2 at their promoters by performing ChIP-Seq experiments. Stratification of gene expression and genome-wide pairwise comparison of KDM5C binding will identify direct KDM5C target genes. The results will provide epigenetic insights into how the down-regulation or inhibition of KDM5C may increase expression of metastasis-linked genes to enhance the invasive ability of prostate cancer cells. To gain new insight into KDM5C-mediated gene regulation we want to search for KDM5C-interacting proteins. Affinity purification and a mass spectrometric analysis of KDM5C-associated proteins will allow identifying unknown KDM5C-interacting proteins. The data emerging from this project will improve the knowledge about the molecular mechanisms taking place during development of metastatic prostate cancer and will answer the question whether targeting KDM5C is a strategy to reduce metastatic burden.