Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming.

A new interesting article has been published in Gut. 2019 Jul;68(7):1271-1286. doi: 10.1136/gutjnl-2017-315690. Epub 2018 Oct 18. Research Support, N.I.H., Extramural and titled:

Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming.

Authors of this article are:

Koutsioumpa M, Hatziapostolou M, Polytarchou C, Tolosa EJ, Almada LL, Mahurkar-Joshi S, Williams J, Tirado-Rodriguez AB, Huerta-Yepez S, Karavias D, Kourea H, Poultsides GA, Struhl K, Dawson DW, Donahue TR, Fernández-Zapico ME, Iliopoulos D.

A summary of the article is shown below:

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 characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.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 five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.RESULTS: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour 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 tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Check out the article’s website on Pubmed for more information:

[link-preview url=https://www.ncbi.nlm.nih.gov/pubmed/30337373 forceshot=true]

This article is a good source of information and a good way to become familiar with topics such as: Animals;Carcinoma;Case-Control Studies;Cell Culture Techniques;Disease Models, Animal;Histone Demethylases;Histone-Lysine N-Methyltransferase;Humans;Mice;Neoplasm Transplantation;Pancreatic Neoplasms.

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