Downregulation ofGLS2in glioblastoma cells is related to DNA hypermethylation but not to the p53 status

Abstract

Human phosphate-activated glutaminase (GA) is encoded by two genes: GLS and GLS2. Glioblastomas (GB) usually lack GLS2 transcripts, and their reintroduction inhibits GB growth. The GLS2 gene in peripheral tumors may be i) methylation- controlled and ii) a target of tumor suppressor p53 often mutated in gliomas. Here we assessed the relation of GLS2 downregulation in GB to its methylation and TP53 status. DNA demethylation with 5-aza-2'-deoxycytidine restored GLS2 mRNA and protein content in human GB cell lines with both mutated (T98G) and wild-type (U87MG) p53 and reduced the methylation of CpG1 (promoter region island), and CpG2 (first intron island) in both cell lines. In cell lines and clinical GB samples alike, methylated CpG islands were detected both in the GLS2 promoter (as reported earlier) and in the first intron of this gene. CpG methylation of either island was absent in GLS2-expressing non-tumoros brain tissues. Screening for mutation in the exons 5-8 of TP53 revealed a point mutation in only one out of seven GB examined. In conclusion, aberrant methylation of CpG islands, appear to contribute to silencing of GLS2 in GB by a mechanism bypassing TP53 mutations. © 2015 Wiley Periodicals, Inc.

From Krebs to clinic: glutamine metabolism to cancer therapy

“…In contrast, the role of GLS2 in cancer seems more complex. Silenced by promoter methylation in liver cancer, colorectal cancer and glioblastoma, re-expression of GLS2 has been shown to have tumor suppressor activities in colony formation assays 55–59 . In fact, a recent studied showed that GLS2, in a non-metabolic function, sequesters the small GTPase RAC1 to suppress metastasis 60 .…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…In contrast, the role of GLS2 in cancer seems more complex. Silenced by promoter methylation in liver cancer, colorectal cancer and glioblastoma, re-expression of GLS2 has been shown to have tumor suppressor activities in colony formation assays [55][56][57][58][59] . In fact, a recent studied showed that GLS2, in a nonmetabolic function, sequesters the small GTPase RAC1 to suppress metastasis 60 .…”

Loss of GLS2 function is essential for obtaining oncogenic functions and promotes the progression of clear cell renal cell carcinoma.

“…GLS2, which is also called liver-type glutaminase, is primarily expressed in liver, pancreas and brain tissue [27]. Previous studies have proven that GLS2 serves as a tumor suppressor in liver and brain cancer [28,29]. GLS2 is a target gene of p53 [30] and is related to DNA hypermethylation.…”