Shuttling SLC2A4RG is Regulated by 14-3-3θ¸ to Modulate Cell Survival Via Caspase-3 and Caspase-6 in Human Glioma

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. In this study, we revealed that nuclear SLC2A4RG was significantly decreased in human glioma specimens and associated with patients' unfavorable prognosis. 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, therefore, identify a new pro-oncogenic mechanism whereby 14-3-3I¸ negatively regulates the nuclear function of the tumor suppressor SLC2A4RG, with significant therapeutic implications for the intervention of human glioma. Funding: This work was supported by the National Natural Science Foundation of China (81372706, 81572501, 81071739, 81372235, and 81201978). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: The present study was approved by the Ethical Review Committee of SMMU.