KMT9 is an actionable target in muscle-invasive bladder cancer
Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified lysine methyltransferase (KMT) 9, an obligate heterodimer composed of KMT9a and KMT9ß, regulates the growth of various types of tumors such as prostate, lung and colon cancer. While overexpression of KMT9a was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients' tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date. In this study, we show that KMT9 regulates proliferation and migration of various MIBC cell lines with different genetic mutations. KMT9a depletion results in differential expression of genes involved in the regulation of the cell cycle, cell adhesion and migration. Reduced cell proliferation upon KMT9a depletion is also observed in Pten/Trp53 knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9a mutant. In accordance with the idea that the catalytic activity of KMT9 is required for the control of cellular processes in MIBC, a recently developed small molecule inhibitor of KMT9 (KMI169) also impairs cancer cell proliferation. Since KMT9a depletion also restricts the growth of xenografts in mice, our data suggest that KMT9 is an actionable novel therapeutic target for the treatment of MIBC. Overall design: To investigate the role of KMT9 on BC cell transcriptome, we treated 5637 and CAL-29 cells with an siRNA for KMT9a depletion (siRNA) and a control siRNA (siCT). We then performed gene expression profiling analysis using data obtained from RNA-seq of the cells treated as described. Comparative gene expression profiling analysis of RNA-seq data for samples from siCT and siRNA treated cells.