The histone Lysine Methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming

OBJECTIVE: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterize the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumorigenesis. DESIGN: DNA Methylation Sequencing and Gene Expression Microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in 5 cohorts of patients by qRT-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using a XF24–3 Analyzer, while quantitative evaluation of lipids was performed by LC-MS analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumor growth in vivo. RESULTS: We define a new antitumoral function of the histone Lysine (K)-Specific Methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumors through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumor growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular metabolic and proliferative rates. CONCLUSION: Together our findings define a new tumor suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.