Reciprocal Regulation of Transketolase-like 1 and Hypoxia-inducible Factor 1 Alpha in Metabolic Reprogramming and Growth of Diffuse Midline Glioma, H3 K27M-mutant
Abstract
Diffuse midline glioma, K27M-mutant (DMG) are intractable brain tumors, primarily occurring in the pediatric and adolescent population. Patients have a median survival of less than one year after diagnosis. A lack of therapeutic targets has been a barrier to improvement in patient survival. Irradiation therapy improves symptoms while chemotherapy and surgical intervention, for the most part, have not yet demonstrated utility for treatment. DMG are characterized by a histone H3 mutation that results in the genome-wide loss of epigenetic-repressive marks on K27 and is associated with the misexpression of genes, like Cancer/Testis antigens. A member of this group, transketolase-like 1 (TKTL1), is an enzyme that catalyzes reactions bridging glycolysis and the pentose phosphate pathway. This work demonstrates that DMG express TKTL1, which reprograms cellular metabolism in support of tumor cell growth and regulates the expression of hypoxia-inducible factor 1 alpha (HIF-1α). HIF-1α in tumor cells is associated with increased invasion, metastasis, increased survival, and resistance to therapy. Inhibition of HIF-1α in DMG cells decreased hypoxia-induced gene expression, glycolytic capacity, mitochondrial respiration, and tumor cell proliferation. TKTL1 knockdown similarly reduced tumor cell proliferation and the population of mitotic cells and decreased glycolytic rate. Loss of TKTL1 did not increase sensitivity to the chemotherapeutic agents, panobinostat or carboplatin, but rather slowed DMG cell growth independently of their cytotoxic effects. These data indicate TKTL1 expression in DMG alters metabolism and proliferation and is a potential therapeutic target.
