Genome Integrity and Reprogrammed Metabolism in H3.3K27M High-grade Gliomas

Pediatric high-grade gliomas (pHGG) are an extremely aggressive subtype of childhood brain cancer, with a survival rate of less than one year after diagnosis. Accumulated evidence demonstrated that mutations (changes) in the histone H3.3 protein occur in 35% of pHGG cases, and a specific mutation, entitled H3.3K27M, accounts for 50% of them. However, despite extensive knowledge, no adequate therapeutic option is currently available, and prognosis of pHGG remains dismal. To unravel new therapeutic opportunities for H3.3K27M pHGGs, we investigated the underlying mechanisms behind their loss of genome (collection of genes in an organism) integrity and metabolic reprogramming. Of note, genome integrity refers to the preservation of cellular DNA without mutations. Whenever it is compromised, DNA damage is passed from paternal cells to their offspring, accumulating and growing in each cell generation, a process known as genomic instability. Meanwhile, metabolic reprogramming concerns the deviation of normal cell metabolism, through (de)activation of metabolic pathways, to fulfill the intense metabolic demands of highly proliferative cancer cells. We demonstrated that H3.3K27M compromises genome integrity by disrupting the normal process of DNA replication and blocking DNA repair mechanisms, leading to genomic instability and causing cancer. Furthermore, we showed that the H3.3K27M mutation activates a metabolic pathway named glycolysis, while deactivating another one named oxidative phosphorylation, to fuel intense cell proliferation. Additionally, we observed that inhibition of PFKFB3, a pivotal enzyme that participates in glycolysis, eliminates H3.3K27M mutant cells. In summary, we described previously unknown oncogenic mechanisms of H3.3K27M pHGGs and identified potential novel therapeutic opportunities.