Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P ¼ 0.029) and 19.9 versus 11.8 months (P ¼ 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G 0 -G 1 . RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D

<p>Expression of KMT2D and KMT2C, where KMT2C depletion by targeted siRNAs has a significant impact upon cell proliferation and cell cycle.</p>

<p>Correlations of gene expression and patient survival.</p>

<p>Analysis of PDAC tumors from the ICGA and TCGA datasets suggests that lower KMT2C and KMT2D expression may correlate with improved patient survival.</p>

<p>Confirmation of gene knockdown at the exon level, and correlations between the multiple siRNAs, for both KMT2C and KMT2D within the RNA-seq data.</p>

<p>Changes in RPKM expression for selected genes identified by RNA-seq, and global levels of H3K4 methylation, following depletion of KMT2D or KMT2C by siRNA.</p>

<p>Depletion of Kmt2d and Kmt2c does not affect the viability of murine pancreatic cancer cells, and Kmt2c depletion does not affect sensitivity to 5FU.</p>

<p>Tables containing supplemental data for Table S1 to Table S9</p>