Shuttling SLC2A4RG is regulated by 14-3-3θ to modulate cell survival via caspase-3 and caspase-6 in human glioma.

Abstract

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:

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:

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).

• Authors: Dapeng Yun, Hongxiang Wang, Yuqi Wang, Yuanyuan Chen, Zhipeng Zhao, Jiawei Ma, Yuanyuan Ji, Qilin Huang, Juxiang Chen, Hongyan Chen, Daru Lu
• Journal: EBioMedicine (EBioMedicine) Vol. 40 Pg. 163-175 (Feb 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30686753 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• 14-3-3 Proteins
• Biomarkers, Tumor
• DNA-Binding Proteins
• SLC2A4RG protein, human
• Transcription Factors
• Caspase 3
• Caspase 6

Topics

• 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, metabolism, mortality, pathology)
• Heterografts
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Mice
• Models, Molecular
• Prognosis
• Protein Transport
• Transcription Factors (genetics)