title: G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation.
abstract: Methylation of histone H3-lysine 9 (H3K9) and H3K27 by the methyltransferase G9a and polycomb repressive complex 2 (PRC2) inhibits transcription of target genes. A crosstalk between G9a and PRC2 via direct physical interaction has been shown recently. Here, we demonstrate an alternative mechanism by which G9a promotes H3K27 methylation. Overexpression of G9a increases both H3K9 and H3K27 methylation, reduces E-cadherin expression, and induces epithelial-mesenchymal transition in PANC-1 pancreatic cancer cells. Conversely, the depletion of G9a or ectopic expression of methyltransferase-dead G9a in G9a-overexpressing gemcitabine-resistant PANC-1-R cells exhibits opposite effects. G9a promotes H3K27 methylation of the E-cadherin promoter by upregulating PCL3 to increase PRC2 promoter recruitment and by downregulating the H3K27 demethylase KDM7A to silence E-cadherin gene. The depletion of PCL3 or overexpression of KDM7A elevated expression of E-cadherin in PANC-1-R cells while ectopic expression of PCL3 or knockdown of KDM7A downregulated E-cadherin in PANC-1 cells. Collectively, we provide evidence that G9a orchestrates the dynamic balance within histone-modifying enzymes to regulate H3K27 methylation and gene expression.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 804, Taiwan.
authors.forename: Mei-Ren
authors.initials: MR
authors.lastname: Pan
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D015820:Cadherins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D008745:Methylation; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D006649:Histocompatibility Antigens; D009687:Nuclear Proteins; C497703:PHF19 protein, human; D014157:Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C548973:KDM7A protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase