Shuttling SLC2A4RG is regulated by 14-3-3θ to modulate cell survival via caspase-3 and caspase-6 in human gliomaResearch in context
Dapeng Yun,
Hongxiang Wang,
Yuqi Wang,
Yuanyuan Chen,
Zhipeng Zhao,
Jiawei Ma,
Yuanyuan Ji,
Qilin Huang,
Juxiang Chen,
Hongyan Chen,
Daru Lu
Affiliations
Dapeng Yun
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
Hongxiang Wang
Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Yuqi Wang
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
Yuanyuan Chen
Department of Critical Care Medicine, Wuxi No’2 People's Hospital, Wuxi, Jiangsu Province, China
Zhipeng Zhao
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
Jiawei Ma
Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Yuanyuan Ji
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
Qilin Huang
Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Juxiang Chen
Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; Corresponding author at: Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Hongyan Chen
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China; Corresponding authors at: School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200438, China.
Daru Lu
State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China; Corresponding authors at: School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200438, China.
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). Keywords: Glioma, Prognosis, Apoptosis, SLC2A4RG, 14-3-3θ
