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


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas.
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France.
Nicolas
N
Girard
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France; Service d'Anatomie Pathologique, CHU, Caen, France.
Céline
C
Bazille
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France.
Eva
E
Lhuissier
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France; Service de Chirurgie Maxillo-faciale, CHU, Caen, France.
Hervé
H
Benateau
Pathology Department, University of Valencia, Valencia, Spain.
Antonio
A
Llombart-Bosch
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France.
Karim
K
Boumediene
Normandie Univ, Caen, France; UNICAEN, EA4652 MILPAT, Caen, France.
Catherine
C
Bauge
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002813:Chondrosarcoma / Q000201:enzymology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004791:Enzyme Inhibitors; C048460:3-deazaneplanocin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine