Search

Background: Glucose metabolic reprogramming is a significant hallmark of malignant tumors including GBM. Previous studies suggest that microRNAs play key roles in modulating this process in GBM cells. miR-181b acts as a tumor suppressor miRNA in influencing glioma tumorigenesis. Our previous results showed that miR-181b was down-regulated in glioma cells and tissues. Methods: The extracellular acidification rate (ECAR), colony formation assay and levels of Glut1 and PKM2 were measured to assess the glucose metabolic and proliferation changes in GBM cells overexpressing miR-181b. Immunoblotting and luciferase reporter assay were performed to confirm the expression and role of SP1 as a direct target of miR-181b. ChIP assay was used to figure out the transcriptional regulation of SP1 on Glut1 and PKM2. In vivo study was examined for the role of miR-181b in GBM cells. Results: MiR-181b overexpression significantly reduced the glucose metabolic and colony formation ability of GBM cells. And, SP1 was confirmed as a direct target of miR-181b while upregulation of SP1 could reverse the influence of overexpression of miR-181b. Furthermore, Glut1 and PKM2 could be regulated by SP1. Finally, miR-181b could inhibit the tumor growth in vivo. Conclusions: Our article demonstrated the inhibitory effect of miR-181b on glucose metabolism and proliferation in GBM by suppressing SP1 expression. [ABSTRACT FROM AUTHOR]

Cancer-specific TERT promoter mutations have been linked to the reactivation of epigenetically silenced TERT gene by creating de novo binding motifs for E-Twenty-Six transcription factors, especially GABPA. How these mutations switch on TERT from epigenetically repressed states to expressed states have not been defined. Here, we revealed that EGFR activation induces ERK1/2-dependent phosphorylation of argininosuccinate lyase (ASL) at Ser417 (S417), leading to interactions between ASL and GABPA at the mutant regions of TERT promoters. The ASL-generated fumarate inhibits KDM5C, leading to enhanced trimethylation of histone H3 Lys4 (H3K4me3), which in turn promotes the recruitment of c-Myc to TERT promoters for TERT expression. Expression of ASL S417A, which abrogates its binding with GABPA, results in reduced TERT expression, inhibited telomerase activity, shortened telomere length, and impaired brain tumor growth in mice. This study reveals an unrecognized mechanistic insight into epigenetically activation of mutant TERT promoters where GABPA-interacted ASL plays an instrumental role. [Display omitted] • GABPA binds with S417-phosphorylated ASL and directs ASL to mutant TERT promoter • ASL-generated fumarate enhances H3K4me3 at mutant TERT promoter by inhibiting KDM5C • GABPA/ASL interaction is prerequisite for recruiting c-Myc to mutant TERT promoter • ASL S417 phosphorylation promotes TERT expression and GBM tumorigenesis Shi et al. report that through interacting with GABPA, S417-phosphorylated ASL locates on mutant regions of TERT promoters, where it generates fumarate to inhibit KDM5C and subsequently facilitates enrichment of H3K4me3 in these regions. This event promotes the recruitment of c-Myc for TERT transcription and GBM tumorigenesis. [ABSTRACT FROM AUTHOR]