LAUSR

Introduction Prostate cancer (PCa) is the most frequently diagnosed malignancy in men and ranks as the third leading cause of cancer-related death in Western civilization. There is an urgent need to provide diagnostic tools able to reliably stratify aggressive from slow progressing tumours. As a result, over-diagnosis of PCa remains a prevalent issue and patients frequently suffer from severe side effects following therapeutic intervention. Recently, whole-exome sequencing has identified the MLL family member KMT2C amongst the most frequently mutated genes in human prostate cancer. However, the exact role of this histone lysine methyltransferase in tumorigenesis remains elusive. In this study we aim to investigate the contribution of the methyltransferase activity of Kmt2c to prostate tumorigenesis using a Pten-deficient mouse model of PCa. Material and methods We have developed a mouse model with a double deletion of the tumour suppressor Pten and the methyltransferase domain of Kmt2c in the prostate epithelium (PtenKmt2cPE-/-). Mice were sacrificed at 19 weeks of age and prostate tissue was analysed according to size, morphology and selected markers involved in tumorigenesis in comparison to Pten-deficient control mice (PtenPE-/-). To establish human relevance, we investigated the correlation of KMT2C expression to biochemical recurrence (BCR) and exploited publicly available databases to gain insight from the mutational frequency spectrum of KMT2C in PCa. Results and discussions Deletion of the Kmt2c methyltransferase activity (PtenKmt2cPE-/-) resulted in severely reduced life expectancy, increased tumour size and weight accompanied by a more aggressive histopathological morphology. PtenKmt2cPE-/- tumours showed increased proliferation rates and a deregulation of several histone marks. In a dataset of human PCa patients we found that low expression as well as truncating mutations of KMT2C are similarly associated with poor prognosis. Analysis of TMAs of human PCa patients showed decreased KMT2C expression in bad prognostic high Gleason grade PCa tumour samples. Conclusion Our findings indicate that loss of Kmt2c methyltransferase activity accelerates PCa tumorigenesis in the PtenKmt2cPE-/- mouse model as well as in human patient samples. We therefore propose Kmt2c as a tumour suppressor in prostate cancer.