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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]

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K M of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM , TFB1M , and TFB2M , resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis. • Hypoxia suppresses mitochondrial biogenesis of tumor cells • PGC-1α's activity is inhibited by K224 monomethylation under hypoxic conditions • KDM3A senses oxygen availability for its activity and demethylates PGC-1α • PGC-1α monomethylation reduces hypoxia-induced ROS and apoptosis for tumor growth Qian et al. demonstrated that KDM3A functions as an oxygen sensor and demethylates K224-monomethylated PGC-1α under normoxic conditions. Hypoxia inhibits KDM3A activity and increases PGC-1α K224 monomethylation, resulting in the inhibition of PGC-1α and PGC-1α-dependent mitochondrial biogenesis, a decrease of ROS levels and apoptosis, and the promotion of brain tumor development. [ABSTRACT FROM AUTHOR]