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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]

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy. [Display omitted] • Fumarate directly targets and succinates PTEN at C211 • C211 succination abrogates the interaction of PTEN with the cellular membrane • PTEN C211 succination is positively correlated with PI3K/AKT activation in PRCC2 • Inhibiting PTEN C211 succination or AKT sensitizes PRCC2 to sunitinib treatment Ge et al. report that fumarate, an oncometabolite, succinates PTEN at C211, which abrogates the binding of PTEN with the cellular membrane. C211 succination of PTEN thereby activates PI3K/AKT signaling and promotes tumor growth of PRCC2. Inhibiting PTEN C211 succination or AKT activation enhances sensitivity of PRCC2 to sunitinib treatment. [ABSTRACT FROM AUTHOR]