ELF4 is a critical component of a miRNA-transcription factor network and is a bridge regulator of glioblastoma receptor signaling and lipid dynamics.
Humans
Transcription Factors
/ genetics
Glioblastoma
/ pathology
MicroRNAs
/ genetics
Receptor Protein-Tyrosine Kinases
/ genetics
Gene Expression Regulation, Neoplastic
Lipids
Cell Proliferation
Cell Line, Tumor
Brain Neoplasms
/ pathology
DNA-Binding Proteins
/ genetics
Protein-Tyrosine Kinases
/ metabolism
ELF4
RTK signaling
glioblastoma
lipid dynamics
miRNA-transcription factor networks
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
14 03 2023
14 03 2023
Historique:
pubmed:
22
7
2022
medline:
17
3
2023
entrez:
21
7
2022
Statut:
ppublish
Résumé
The loss of neurogenic tumor suppressor microRNAs miR-124, miR-128, and miR-137 is associated with glioblastoma's undifferentiated state. Most of their impact comes via the repression of a network of oncogenic transcription factors. We conducted a high-throughput functional siRNA screen in glioblastoma cells and identify E74 like ETS transcription factor 4 (ELF4) as the leading contributor to oncogenic phenotypes. In vitro and in vivo assays were used to assess ELF4 impact on cancer phenotypes. We characterized ELF4's mechanism of action via genomic and lipidomic analyses. A MAPK reporter assay verified ELF4's impact on MAPK signaling, and qRT-PCR and western blotting were used to corroborate ELF4 regulatory role on most relevant target genes. ELF4 knockdown resulted in significant proliferation delay and apoptosis in GBM cells and long-term growth delay and morphological changes in glioma stem cells (GSCs). Transcriptomic analyses revealed that ELF4 controls two interlinked pathways: 1) Receptor tyrosine kinase signaling and 2) Lipid dynamics. ELF4 modulation directly affected receptor tyrosine kinase (RTK) signaling, as mitogen-activated protein kinase (MAPK) activity was dependent upon ELF4 levels. Furthermore, shotgun lipidomics revealed that ELF4 depletion disrupted several phospholipid classes, highlighting ELF4's importance in lipid homeostasis. We found that ELF4 is critical for the GBM cell identity by controlling genes of two dependent pathways: RTK signaling (SRC, PTK2B, and TNK2) and lipid dynamics (LRP1, APOE, ABCA7, PLA2G6, and PITPNM2). Our data suggest that targeting these two pathways simultaneously may be therapeutically beneficial to GBM patients.
Sections du résumé
BACKGROUND
The loss of neurogenic tumor suppressor microRNAs miR-124, miR-128, and miR-137 is associated with glioblastoma's undifferentiated state. Most of their impact comes via the repression of a network of oncogenic transcription factors. We conducted a high-throughput functional siRNA screen in glioblastoma cells and identify E74 like ETS transcription factor 4 (ELF4) as the leading contributor to oncogenic phenotypes.
METHODS
In vitro and in vivo assays were used to assess ELF4 impact on cancer phenotypes. We characterized ELF4's mechanism of action via genomic and lipidomic analyses. A MAPK reporter assay verified ELF4's impact on MAPK signaling, and qRT-PCR and western blotting were used to corroborate ELF4 regulatory role on most relevant target genes.
RESULTS
ELF4 knockdown resulted in significant proliferation delay and apoptosis in GBM cells and long-term growth delay and morphological changes in glioma stem cells (GSCs). Transcriptomic analyses revealed that ELF4 controls two interlinked pathways: 1) Receptor tyrosine kinase signaling and 2) Lipid dynamics. ELF4 modulation directly affected receptor tyrosine kinase (RTK) signaling, as mitogen-activated protein kinase (MAPK) activity was dependent upon ELF4 levels. Furthermore, shotgun lipidomics revealed that ELF4 depletion disrupted several phospholipid classes, highlighting ELF4's importance in lipid homeostasis.
CONCLUSIONS
We found that ELF4 is critical for the GBM cell identity by controlling genes of two dependent pathways: RTK signaling (SRC, PTK2B, and TNK2) and lipid dynamics (LRP1, APOE, ABCA7, PLA2G6, and PITPNM2). Our data suggest that targeting these two pathways simultaneously may be therapeutically beneficial to GBM patients.
Identifiants
pubmed: 35862252
pii: 6648020
doi: 10.1093/neuonc/noac179
pmc: PMC10013642
doi:
Substances chimiques
Transcription Factors
0
MicroRNAs
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Lipids
0
ELF4 protein, human
0
DNA-Binding Proteins
0
TNK2 protein, human
EC 2.7.10.2
Protein-Tyrosine Kinases
EC 2.7.10.1
MIRN137 microRNA, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
459-470Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG006015
Pays : United States
Organisme : NIH HHS
ID : S10 OD021805
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA054174
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS113344
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Cell Stem Cell. 2012 Dec 7;11(6):836-44
pubmed: 23217424
Sci Rep. 2021 Jan 11;11(1):430
pubmed: 33432099
Cancer Res. 2016 Apr 15;76(8):2465-77
pubmed: 26896279
Nature. 1996 Oct 10;383(6600):547-50
pubmed: 8849729
Cancer Cell. 2006 Mar;9(3):175-87
pubmed: 16530702
Cancer. 2019 Nov 1;125(21):3790-3800
pubmed: 31290996
J Cell Biol. 1993 Sep;122(5):1013-22
pubmed: 8354691
NPJ Genom Med. 2020 Jan 16;5:2
pubmed: 31969990
Cancers (Basel). 2021 Jan 14;13(2):
pubmed: 33466745
Nat Rev Neurosci. 2009 May;10(5):333-44
pubmed: 19339974
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8644-9
pubmed: 23650391
J Biol Chem. 2013 Nov 29;288(48):34414-26
pubmed: 24097981
Anal Biochem. 2008 Jan 15;372(2):204-12
pubmed: 17963684
Crit Rev Oncol Hematol. 2017 Dec;120:22-33
pubmed: 29198335
Genome Biol. 2016 Jun 10;17(1):125
pubmed: 27287018
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
J Invest Dermatol. 2010 Sep;130(9):2179-90
pubmed: 20428185
Cancer Cell. 2010 Jan 19;17(1):98-110
pubmed: 20129251
Cells. 2020 May 16;9(5):
pubmed: 32429463
Cell. 2010 Jun 25;141(7):1117-34
pubmed: 20602996
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Cancer Res. 2016 Apr 1;76(7):1814-24
pubmed: 26921333
Stem Cells. 2016 Jan;34(1):220-32
pubmed: 26369286
J Mol Signal. 2010 Jul 12;5:8
pubmed: 20624308
Signal Transduct Target Ther. 2017 Sep 29;2:17040
pubmed: 29263927
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9796-801
pubmed: 16777958
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
J Cell Sci. 2014 Mar 1;127(Pt 5):994-1006
pubmed: 24413169
J Biol Chem. 2004 Feb 27;279(9):8212-8
pubmed: 14670955
J Clin Oncol. 2009 Dec 1;27(34):5743-50
pubmed: 19805672
PLoS One. 2010 Sep 23;5(9):e12897
pubmed: 20886109
Cell. 2013 Oct 10;155(2):462-77
pubmed: 24120142
Cancers (Basel). 2019 Oct 22;11(10):
pubmed: 31652660
PLoS One. 2021 Apr 9;16(4):e0248984
pubmed: 33836003
J Cell Physiol. 2012 Nov;227(11):3603-12
pubmed: 22307523
Nat Commun. 2019 Jan 25;10(1):442
pubmed: 30683859
Cell. 2019 Aug 8;178(4):835-849.e21
pubmed: 31327527
Mol Cell Biol. 2001 Oct;21(19):6387-94
pubmed: 11533228
Mol Oncol. 2015 Aug;9(7):1324-40
pubmed: 25864039
Cancer Discov. 2019 Sep;9(9):1248-1267
pubmed: 31201181
Cell Metab. 2019 Sep 3;30(3):525-538.e8
pubmed: 31303424
Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):
pubmed: 23125017
Nat Rev Mol Cell Biol. 2017 Jun;18(6):361-374
pubmed: 28356571
Sci Signal. 2012 Nov 06;5(249):pe49
pubmed: 23131845
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Bioinformatics. 2016 Sep 15;32(18):2866-8
pubmed: 27153664
Mol Cell Biol. 1999 Mar;19(3):2278-88
pubmed: 10022914
Mol Cancer Res. 2020 Jan;18(1):68-78
pubmed: 31624087
Mol Genet Genomics. 2013 Apr;288(3-4):77-87
pubmed: 23334784