Liu Juan, Zhang Cen, Lin Meihua, Zhu Wei, Liang Yingjian, Hong Xuehui, Zhao Yuhan, Young Ken H, Hu Wenwei, Feng Zhaohui
Department of Radiation Oncology.
Oncotarget. 2014 May 15;5(9):2635-47. doi: 10.18632/oncotarget.1862.
The tumor suppressor p53 and its signaling pathway play a critical role in tumor prevention. As a direct p53 target gene, the role of glutaminase 2 (GLS2) in tumorigenesis is unclear. In this study, we found that GLS2 expression is significantly decreased in majority of human hepatocellular carcinoma (HCC). Restoration of GLS2 expression in HCC cells inhibits the anchorage-independent growth of cells and reduces the growth of HCC xenograft tumors. Interestingly, we found that GLS2 negatively regulates the PI3K/AKT signaling, which is frequently activated in HCC. Blocking the PI3K/AKT signaling in HCC cells largely abolishes the inhibitory effect of GLS2 on the anchorage-independent cell growth and xenograft tumor growth. The GLS2 promoter is hypermethylated in majority of HCC samples. CpG methylation of GLS2 promoter inhibits GLS2 transcription, whereas reducing the methylation of GLS2 promoter induces GLS2 expression. Taken together, our results demonstrate that GLS2 plays an important role in tumor suppression in HCC, and the negative regulation of PI3K/AKT signaling contributes greatly to this function of GLS2. Furthermore, hypermethylation of GLS2 promoter is an important mechanism contributing to the decreased GLS2 expression in HCC.
肿瘤抑制因子p53及其信号通路在肿瘤预防中发挥着关键作用。作为p53的直接靶基因，谷氨酰胺酶2（GLS2）在肿瘤发生中的作用尚不清楚。在本研究中，我们发现大多数人类肝细胞癌（HCC）中GLS2的表达显著降低。在HCC细胞中恢复GLS2表达可抑制细胞的非锚定依赖性生长，并减少HCC异种移植瘤的生长。有趣的是，我们发现GLS2负向调节PI3K/AKT信号通路，该信号通路在HCC中经常被激活。阻断HCC细胞中的PI3K/AKT信号通路在很大程度上消除了GLS2对非锚定依赖性细胞生长和异种移植瘤生长的抑制作用。大多数HCC样本中GLS2启动子发生高甲基化。GLS2启动子的CpG甲基化抑制GLS2转录，而降低GLS2启动子的甲基化则诱导GLS2表达。综上所述，我们的结果表明GLS2在HCC的肿瘤抑制中发挥重要作用，PI3K/AKT信号通路的负向调节对GLS2的这一功能有很大贡献。此外，GLS2启动子的高甲基化是导致HCC中GLS2表达降低的重要机制。
