Abstract
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.
Highlights
We further investigated whether negative regulation of the PI3K/AKT signaling by Glutaminase 2 (GLS2) contributes to GLS2’s role in tumor suppression in hepatocellular carcinoma (HCC)
We found that the GLS2 protein expression was significantly decreased in majority of primary HCCs that we examined compared with nontumor liver tissues, including liver tissues with cirrhosis and hepatitis (Supplementary Table S2)
These results clearly demonstrated that the down-regulation of GLS2 is a common event in primary HCCs, which has the potential to be developed as a biomarker for early detection and diagnosis of HCCs
Summary
Tumor suppressor p53 plays a crucial role in tumor prevention, including hepatocellular carcinoma (HCC) [1,2,3]. p53 is the most frequently-mutated gene in human tumors; over 50% of human tumors harbor mutations in the p53 gene. P53 mainly exerts its tumor suppression function through its transcriptional regulation of its downstream target genes. Through the regulation of the expression of many downstream target genes, p53 regulates cell cycle arrest, apoptosis, senescence, cellular energy metabolism and anti-oxidant defense, all of which contribute to the role of p53 in tumor suppression [1,2,3, 8]. GLS2 mediates the functions of p53 in www.impactjournals.com/oncotarget regulation of energy metabolism and anti-oxidant defense [11, 12]. Considering the critical role of p53 and its pathway in tumor suppression, as a novel p53 target gene, GLS2 might play an important role in tumor suppression. The role of GLS2 in tumorigenesis is not wellunderstood
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