Shuttling SLC2A4RG is regulated by 14-3-3 theta to modulate cell survival via caspase-3 and caspase-6 in human glioma
Shuttling SLC2A4RG is regulated by 14-3-3 theta to modulate cell survival via caspase-3 and caspase-6 in human glioma
复制标题
在人胶质瘤中，穿梭 SLC2A4RG 受 14-3-3 theta 调节，通过 caspase-3 和 caspase-6 调节细胞存活
DOI：
10.1016/j.ebiom.2019.01.030
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Lu Daru
中科院分区：
文献类型：
--
作者：
Yun Dapeng;Wang Hongxiang;Wang Yuqi;Chen Yuanyuan;Zhao Zhipeng;Ma Jiawei;Ji Yuanyuan;Huang Qilin;Chen Juxiang;Chen Hongyan;Lu Daru
背景胶质瘤是最常见、最具侵袭性的原发脑肿瘤，具有多基因易感性。通过全基因组关联研究和精细定位分析，在影响脑胶质瘤易感性的20q13.33区域发现了细胞质/核穿梭蛋白SLC2A4RG(SLC2A4RG)。通过体内功能获得和功能丧失分析评价SLC2A4RG对细胞增殖、细胞周期和细胞凋亡的影响，并通过皮下和颅内移植来评价其功能效应。通过荧光素酶报告分析、芯片、质谱学、共IP、免疫荧光等方法进一步研究了SLC2A4RG的作用机制。体外实验和体内实验进一步证实了SLC2A4RG通过G2/M期阻滞抑制细胞增殖，并通过直接反式激活caspase-3和caspase-6诱导胶质瘤细胞凋亡。此外，其功能的显示依赖于SLC2A4RG的核转运，但与14-3-3θ结合后，它会滞留在细胞质中，继而产生逆转效应。说明14-3-3θ负性调节抑癌基因SLC2A4RG的核功能是一种新的致癌机制，对人类胶质瘤的干预具有重要的治疗意义。本研究得到国家自然科学基金中国(81372706,81572501,81372235)的资助。
BackgroundGlioma 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.MethodsTo 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 assaysin 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.FindingsThe potential tumor suppressor role of SLC2A4RG was further validated byin vitroandin vivoexperiments 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.InterpretationWe 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.FundThis work was supported by the National Natural Science Foundation of China (81372706, 81572501, and 81372235).