title: EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity.
abstract: The role of enhancer of zeste homolog 2 (EZH2) in cancer is complex and may vary depending on the cellular context. We found that EZH2 is aberrantly overexpressed in the majority of natural killer/T-cell lymphoma (NKTL), an aggressive lymphoid malignancy with very poor prognosis. We show that EZH2 upregulation is mediated by MYC-induced repression of its regulatory micro RNAs and EZH2 exerts oncogenic properties in NKTL. Ectopic expression of EZH2 in both primary NK cells and NKTL cell lines leads to a significant growth advantage. Conversely, knock-down of EZH2 in NKTL cell lines results in cell growth inhibition. Intriguingly, ectopic EZH2 mutant deficient for histone methyltransferase activity is also able to confer growth advantage and rescue growth inhibition on endogenous EZH2 depletion in NKTL cells, indicating an oncogenic role of EZH2 independent of its gene-silencing activity. Mechanistically, we show that EZH2 directly promotes the transcription of cyclin D1 and this effect is independent of its enzymatic activity. Furthermore, depletion of EZH2 using a PRC2 inhibitor 3-deazaneplanocin A significantly inhibits growth of NK tumor cells. Therefore, our study uncovers an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL and suggests that targeting EZH2 may have therapeutic usefulness in this lymphoma.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 1E Kent Ridge Road, Singapore.
authors.forename: Junli
authors.initials: J
authors.lastname: Yan
authors.forename: Siok-Bian
authors.initials: SB
authors.lastname: Ng
authors.forename: Jim Liang-Seah
authors.initials: JL
authors.lastname: Tay
authors.forename: Baohong
authors.initials: B
authors.lastname: Lin
authors.forename: Tze Loong
authors.initials: TL
authors.lastname: Koh
authors.forename: Joy
authors.initials: J
authors.lastname: Tan
authors.forename: Viknesvaran
authors.initials: V
authors.lastname: Selvarajan
authors.forename: Shaw-Cheng
authors.initials: SC
authors.lastname: Liu
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.forename: Shi
authors.initials: S
authors.lastname: Wang
authors.forename: Shoa-Nian
authors.initials: SN
authors.lastname: Choo
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D016296:Mutagenesis / Q000502:physiology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult
chemical_list: D000241:Adenosine; D019938:Cyclin D1; D000071221:Enhancer of Zeste Homolog 2 Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; C530104:CCND1 protein, human; C534072:MIRN101 microRNA, human; C528163:MIRN26 microRNA, human; C048460:3-deazaneplanocin; C498409:EZH2 protein, human