Shuttling SLC2A4RG is regulated by 14-3-3θ to modulate cell survival via caspase-3 and caspase-6 in human glioma.
14-3-3 Proteins
/ metabolism
Animals
Apoptosis
/ genetics
Biomarkers, Tumor
Case-Control Studies
Caspase 3
/ metabolism
Caspase 6
/ metabolism
Cell Cycle
/ genetics
Cell Line, Tumor
Cell Nucleus
/ metabolism
Cell Proliferation
Cell Survival
/ genetics
DNA-Binding Proteins
/ genetics
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Glioma
/ genetics
Heterografts
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Mice
Models, Molecular
Prognosis
Protein Transport
Transcription Factors
/ genetics
14-3-3θ
Apoptosis
Glioma
Prognosis
SLC2A4RG
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Feb 2019
Feb 2019
Historique:
received:
19
09
2018
revised:
10
01
2019
accepted:
11
01
2019
pubmed:
29
1
2019
medline:
27
6
2019
entrez:
29
1
2019
Statut:
ppublish
Résumé
Glioma is the most common and aggressive primary brain tumor with polygenic susceptibility. The cytoplasmic/nuclear shuttling protein, SLC2A4RG (SLC2A4 regulator), has been identified in the 20q13.33 region influencing glioma susceptibility by genome-wide association studies (GWAS) and fine mapping analyses. To discover the expression of SLC2A4RG and its relationship with patient prognosis, tissue microarray containing glioma samples and normal brains was constructed followed by immunohistochemical staining. The role of SLC2A4RG on cell proliferation, cell cycle, and apoptosis was evaluated by gain- and loss-of-function assays in vivo, and subcutaneous and intracranial xenografts were performed to assess its functional effects. The mechanism underlying SLC2A4RG was further investigated via luciferase reporter analyses, ChIP, mass spectrometry, Co-IP, immunofluorescence, etc. FINDINGS: The potential tumor suppressor role of SLC2A4RG was further validated by in vitro and in vivo experiments that SLC2A4RG could attenuate cell proliferation via G2/M phase arrest and induce glioma cell apoptosis by direct transactivation of caspase-3 and caspase-6. Moreover, its function displaying showed to depend on the nuclear transportation of SLC2A4RG, however, bound with 14-3-3θ, it would be sequestered in the cytoplasm followed by reversal effect. We identify a new pro-oncogenic mechanism whereby 14-3-3θ negatively regulates the nuclear function of the tumor suppressor SLC2A4RG, with significant therapeutic implications for the intervention of human glioma. FUND: This work was supported by the National Natural Science Foundation of China (81372706, 81572501, and 81372235).
Sections du résumé
BACKGROUND
BACKGROUND
Glioma is the most common and aggressive primary brain tumor with polygenic susceptibility. The cytoplasmic/nuclear shuttling protein, SLC2A4RG (SLC2A4 regulator), has been identified in the 20q13.33 region influencing glioma susceptibility by genome-wide association studies (GWAS) and fine mapping analyses.
METHODS
METHODS
To discover the expression of SLC2A4RG and its relationship with patient prognosis, tissue microarray containing glioma samples and normal brains was constructed followed by immunohistochemical staining. The role of SLC2A4RG on cell proliferation, cell cycle, and apoptosis was evaluated by gain- and loss-of-function assays in vivo, and subcutaneous and intracranial xenografts were performed to assess its functional effects. The mechanism underlying SLC2A4RG was further investigated via luciferase reporter analyses, ChIP, mass spectrometry, Co-IP, immunofluorescence, etc. FINDINGS: The potential tumor suppressor role of SLC2A4RG was further validated by in vitro and in vivo experiments that SLC2A4RG could attenuate cell proliferation via G2/M phase arrest and induce glioma cell apoptosis by direct transactivation of caspase-3 and caspase-6. Moreover, its function displaying showed to depend on the nuclear transportation of SLC2A4RG, however, bound with 14-3-3θ, it would be sequestered in the cytoplasm followed by reversal effect.
INTERPRETATION
CONCLUSIONS
We identify a new pro-oncogenic mechanism whereby 14-3-3θ negatively regulates the nuclear function of the tumor suppressor SLC2A4RG, with significant therapeutic implications for the intervention of human glioma. FUND: This work was supported by the National Natural Science Foundation of China (81372706, 81572501, and 81372235).
Identifiants
pubmed: 30686753
pii: S2352-3964(19)30035-0
doi: 10.1016/j.ebiom.2019.01.030
pmc: PMC6413354
pii:
doi:
Substances chimiques
14-3-3 Proteins
0
Biomarkers, Tumor
0
DNA-Binding Proteins
0
SLC2A4RG protein, human
0
Transcription Factors
0
Caspase 3
EC 3.4.22.-
Caspase 6
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
163-175Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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