title: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer.
abstract: Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Lois
authors.initials: L
authors.lastname: Dodson
authors.forename: Mithil
authors.initials: M
authors.lastname: Pandhi
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Jung H
authors.initials: JH
authors.lastname: Kim
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.forename: Mathew K
authors.initials: MK
authors.lastname: Iyer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D015533:Transcriptional Activation
chemical_list: D020413:3' Untranslated Regions; D006657:Histones; D035683:MicroRNAs; D012097:Repressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D063151:Polycomb Repressive Complex 2