title: MicroRNA-128 coordinately targets Polycomb Repressor Complexes in glioma stem cells.
abstract: BACKGROUND
  The Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by 2 protein complexes, PRC1 and PRC2. PRC is oncogenic in glioblastoma, where it is involved in cancer stem cell maintenance and radioresistance.
  
  
  METHODS
  We used a set of glioblastoma patient samples, glioma stem cells, and neural stem cells from a mouse model of glioblastoma. We characterized gene/protein expression and cellular phenotypes by quantitative PCR/Western blotting and clonogenic, cell-cycle, and DNA damage assays. We performed overexpression/knockdown studies by lentiviral infection and microRNA/small interfering RNA oligonucleotide transfection.
  
  
  RESULTS
  We show that microRNA-128 (miR-128) directly targets mRNA of SUZ12, a key component of PRC2, in addition to BMI1, a component of PRC1 that we previously showed as a target as well. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stemlike versus neural stem cells. Furthermore, miR-128 renders glioma stemlike cells less radioresistant by preventing the radiation-induced expression of both PRC components. Finally, miR-128 expression is significantly reduced in neural stem cells from the brain of young, presymptomatic mice in our mouse model of glioblastoma. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knockdown of miR-128 expression in nonmalignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity.
  
  
  CONCLUSIONS
  MiR-128 is an important suppressor of PRC activity, and its absence is an early event in gliomagenesis.
authors.affiliation: Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Peruzzi
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Richard
authors.initials: R
authors.lastname: Price
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.forename: Josie
authors.initials: J
authors.lastname: Hayes
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Jakub
authors.initials: J
authors.lastname: Godlewski
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009363:Neoplasm Proteins; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: C069077:BMI1 protein, human; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D063146:Polycomb-Group Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1
keywords: glioblastoma; glioma stem cells; glioma therapy; gliomagenesis; microRNA