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Pancreas
Original article
Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming
  1. Marina Koutsioumpa1,
  2. Maria Hatziapostolou2,3,
  3. Christos Polytarchou4,
  4. Ezequiel J Tolosa5,
  5. Luciana L Almada5,
  6. Swapna Mahurkar-Joshi1,
  7. Jennifer Williams6,
  8. Ana Belen Tirado-Rodriguez7,
  9. Sara Huerta-Yepez7,
  10. Dimitrios Karavias8,
  11. Helen Kourea8,
  12. George A Poultsides9,
  13. Kevin Struhl10,
  14. David W Dawson11,
  15. Timothy R Donahue6,
  16. Martín E Fernández-Zapico5,
  17. Dimitrios Iliopoulos1
  1. 1 Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  2. 2 Biological Sciences, University of Southampton, Southampton, UK
  3. 3 Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
  4. 4 Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
  5. 5 Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA
  6. 6 Department of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  7. 7 Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Mexico City, Mexico
  8. 8 Department of Pathology, School of Medicine, University of Patras, Patras, Greece
  9. 9 Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
  10. 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
  11. 11 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  1. Correspondence to Dr Dimitrios Iliopoulos, Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles 90095, USA; iliopoulospharma{at}gmail.com

Abstract

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.

  • pancreatic cancer
  • molecular oncology
  • gene regulation

https://doi.org/10.1136/gutjnl-2017-315690

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    Footnotes

    • Contributors MK and DI conceived the project and designed the experiments. MK designed and executed most of the experiments. KS designed the chromatin-related experiments. MH and CP assisted in mouse experiments, design/development of the shRNAs, production of lentiviral expressing constructs and cell infections. ABT-R and SH-Y performed the immunohistochemical and digital pathology analysis (cohort IV). Clinical specimens were ascertained and provided by DK, HK, GAP, DWD, and TRD and JW processed all clinical information related to human patients’ cohort III and cohort V, respectively. SM-J performed bioinformatics analysis and generated heatmaps, GO enrichment plots and Venn diagrams. EJT and LLA performed expression and statistical analyses. MK wrote the manuscript, prepared the figures and performed the statistical analyses, and revised by KS, MEF-Z and DI.

    • Funding This study was supported in part by S10RR026744 from the National Center for Research Resources, S10RR027926 from the National Center for Research Resources, CA136526 from the National Institutes of Health, and P30 DK041301/UL1TR000124 from the Center for Ulcer Research and Education Digestive Diseases Research Center and the National Center for Advancing Translational Sciences.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Tissue samples were collected upon IRB approval at the Department of Surgery at Stanford University (cohort I), Department of Pathology and Laboratory Medicine (cohort II), Department of Surgery (cohort III) at UCLA, Department of Pathology at the University of Patras, Greece (cohort IV) and Mayo School of Medicine (cohort V).

    • Provenance and peer review Not commissioned; externally peer reviewed.