3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2, induces apoptosis and reduces cell migration in chondrosarcoma cells

• Published in: PloS one 2014-05, Vol.9 (5), p.e98176-e98176
• Main Authors: Girard, Nicolas, Bazille, Céline, Lhuissier, Eva, Benateau, Hervé, Llombart-Bosch, Antonio, Boumediene, Karim, Bauge, Catherine
• Format: Article
• Language: English
• Subjects: 3-deazaneplanocin; Adenosine - analogs & derivatives; Adenosine - pharmacology; Adherent cells; Analysis; Apoptosis; Apoptosis - drug effects; Biochemistry, Molecular Biology; Biology and Life Sciences; Blotting, Western; Cancer; Cancer therapies; Cell cycle; Cell Death; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell survival; Cellular Biology; Chondrocytes; Chondrosarcoma; Chondrosarcoma - enzymology; Chondrosarcoma - pathology; Cytometry; DNA methylation; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; EZH2 protein, human; Flow Cytometry; Gene expression; Health aspects; Histone H3; Histone methyltransferase; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histones; Homocysteine; Homology; Human health and pathology; Humans; Hydrolase; Hydrolases; Immunohistochemistry; Inhibitors; Leukemia; Life Sciences; Lysine; Medicine and Health Sciences; Metastases; Metastasis; Methyltransferases; Pharmacology; Poly(ADP-ribose) polymerase; Polycomb Repressive Complex 2; Proteins; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Rhumatology and musculoskeletal system; Stem cells; Therapeutic applications; Therapy; Tumors; Wound healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098176

Growing evidences indicate that the histone methyltransferase EZH2 (enhancer of zeste homolog 2) may be an appropriate therapeutic target in some tumors. Indeed, a high expression of EZH2 is correlated with poor prognosis and metastasis in many cancers. In addition, 3-Deazaneplanocin A (DZNep), an S-adenosyl-L homocysteine hydrolase inhibitor which induces EZH2 protein depletion, leads to cell death in several cancers and tumors. The aim of this study was to determine whether an epigenetic therapy targeting EZH2 with DZNep may be also efficient to treat chondrosarcomas. EZH2 expression was determined by immunohistochemistry and western-blot. Chondrosarcoma cell line CH2879 was cultured in the presence of DZNep, and its growth and survival were evaluated by counting adherent cells periodically. Apoptosis was assayed by cell cycle analysis, Apo2.7 expression using flow cytometry, and by PARP cleavage using western-blot. Cell migration was assessed by wound healing assay. Chondrosarcomas (at least with high grade) highly express EZH2, at contrary to enchondromas or chondrocytes. In vitro, DZNep inhibits EZH2 protein expression, and subsequently reduces the trimethylation of lysine 27 on histone H3 (H3K27me3). Interestingly, DZNep induces cell death of chondrosarcoma cell lines by apoptosis, while it slightly reduces growth of normal chondrocytes. In addition, DZNep reduces cell migration. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas.