Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma

Abstract

Background While aerobic glycolysis is linked to unconstrained proliferation in cancer, less is known about its physiological role. Why this metabolic program that promotes tumor growth is preserved in the genome has thus been unresolved. We tested the hypothesis that aerobic glycolysis derives from developmental processes that regulate rapid proliferation. Methods We performed an integrated analysis of metabolism and gene expression in cerebellar granule neuron progenitors (CGNPs) with and without Sonic Hedgehog (Shh), their endogenous mitogen. Because our analysis highlighted Hexokinase-2 (Hk2) as a key metabolic regulator induced by Shh, we studied the effect of conditional genetic Hk2 deletion in CGNP development. We then crossed Hk2 conditional knockout mice with transgenic SmoM2 mice that develop spontaneous medulloblastoma and determined changes in SmoM2-driven tumorigenesis. Results We show that Shh and phosphoinositide 3-kinase (PI3K) signaling combine to induce an Hk2-dependent glycolytic phenotype in CGNPs. This phenotype is recapitulated in medulloblastoma, a malignant tumor of CGNP origin. Importantly, cre-mediated ablation of Hk2 abrogated aerobic glycolysis, disrupting CGNP development and Smoothened-induced tumorigenesis. Comparing tumorigenesis in medulloblastoma-prone SmoM2 mice with and without functional Hk2, we demonstrate that loss of aerobic glycolysis reduces the aggressiveness of medulloblastoma, causing tumors to grow as indolent lesions and allowing long-term survival of tumor bearing mice. Conclusions Our investigations demonstrate that aerobic glycolysis in cancer derives from developmental mechanisms that persist in tumorigenesis. Moreover, we demonstrate in a primary tumor model the anti-cancer potential of blocking aerobic glycolysis by targeting Hk2.

Stem cell metabolism in tissue development and aging

“…Like hematopoietic progenitors, proliferative neural progenitors show high levels of glycolysis mediated by HK2 (Gershon et al, 2013); and like hematopoietic progenitors, the directed differentiation of ESCs into neural progenitors is stimulated by the eicosanoid pathway and also by fatty acid metabolism (Yanes et al, 2010). However, it is unclear whether these effects of fatty acids are due to mitochondrial fatty acid β-oxidation or fatty acid use in lipogenesis, or both.…”

Dengue Virus Induces and Requires Glycolysis for Optimal Replication

“…Hexokinase is the first rate-limiting enzyme of the glycolytic pathway and the HK2 isoform, in particular, has been shown to be a key mediator of aerobic glycolysis (22,28). We utilized real-time RT-qPCR to measure HK2 mRNA levels during DENV infection.…”

Overexpression of ErbB2 renders breast cancer cells susceptible to 3-BrPA through the increased dissociation of hexokinase II from mitochondrial outer membrane

“…Regulation of HK II is involved in glucose or lactate metabolism, and blocking its activity is an effective way of inhibiting glycolysis (10). Glycolysis of cancer cell metabolism is associated with the binding of HK II to the outer mitochondrial membrane protein voltage-dependent anion channel, and this association appears important for mitochondrial homeostasis (10,11). HK II association with the mitochondrial outer membrane is involved in mitochondria-mediated apoptosis and increased resistance of cancer cells to chemotherapeutic drugs (11,12).…”

“…Glycolysis of cancer cell metabolism is associated with the binding of HK II to the outer mitochondrial membrane protein voltage-dependent anion channel, and this association appears important for mitochondrial homeostasis (10,11). HK II association with the mitochondrial outer membrane is involved in mitochondria-mediated apoptosis and increased resistance of cancer cells to chemotherapeutic drugs (11,12). 3-Bromopyruvate (3-BrPA) is a halogenated and alkylating analog of pyruvic acid, and is able to inhibit glycolysis through the dissociation of HK II from mitochondria (13).…”