title: ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1.
abstract: Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia-2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia-1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM.
authors.affiliation: Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Queensland, 4029, Brisbane, Australia. bryan.day@qimr.edu.au
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Day
authors.forename: Brett W
authors.initials: BW
authors.lastname: Stringer
authors.forename: Mark D
authors.initials: MD
authors.lastname: Spanevello
authors.forename: Sara
authors.initials: S
authors.lastname: Charmsaz
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jamieson
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Ensbey
authors.forename: Jacinta C
authors.initials: JC
authors.lastname: Carter
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Cox
authors.forename: Vicky J
authors.initials: VJ
authors.lastname: Ellis
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Brown
authors.forename: David G
authors.initials: DG
authors.lastname: Walker
authors.forename: Po L
authors.initials: PL
authors.lastname: Inglis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Allan
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lickliter
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D050808:ets-Domain Protein Elk-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C494193:ELK4 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D050808:ets-Domain Protein Elk-4; D008156:Luciferases