title: Enhancer of zeste homolog 2 is overexpressed and contributes to epigenetic inactivation of p21 and phosphatase and tensin homolog in B-cell acute lymphoblastic leukemia.
abstract: Enhancer of zeste homolog 2 (EZH2) is crucially involved in epigenetic silencing by acting as a histone methyltransferase. Although EZH2 is overexpressed in many solid cancers, the role of EZH2 in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored. In a microarray experiment, we found that EZH2 was significantly upregulated in Nalm-6 cells and this was associated with the silencing of tumor suppressor genes p21, p53 and phosphatase and tensin homolog (PTEN). The abnormal expression of these genes was further confirmed by quantitative realtime polymerase chain reaction and Western blot analysis on Nalm-6 cells. Chromatin immunoprecipitation assay showed that EZH2 and H3K27me3 were both enriched in the promoter region of PTEN and p21 in Nalm-6 cells but not in normal B cells. Functional analysis showed that siRNA-mediated EZH2 knockdown led to decreased proliferation and increased apoptosis of Nalm-6 cells, accompanied by the reactivation of PTEN and p21 expression. Furthermore, we found that EZH2 inhibitor deazaneplanocin A promoted vincristine sulfate-induced apoptosis of Nalm-6 cells. Taken together, our data suggest that EZH2 is overexpressed in B-ALL and promotes the progression of B-ALL by directly mediating the inactivation of tumor suppressor genes p21 and PTEN, and could serve as a potential epigenetic target for B-ALL therapy.
authors.affiliation: Institute of Basic Medical Sciences & School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005,  China.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Han
authors.forename: Zhao
authors.initials: Z
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.forename: Robert C H
authors.initials: RC
authors.lastname: Zhao
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human