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NOVEL HEXOKINASE-2 ASSOCIATED INFLAMMATORY PROCESSES IN THE GLIOBLASTOMA TUMOUR MICROENVIRONMENT

ABSTRACT: Deregulation of cellular metabolism is a hallmark of cancer, in which tumour cells upregulate glycolysis and preferentially ferment glucose to lactate (rather than pyruvate) in the 'Warburg effect'. Tumour-specific upregulation of hexokinase 2 (HK2), which catalyses the first rate-limiting step of glycolysis, has been established as key to this Warburg metabolism. Interrogating the impact of HK2 expression inhibition upon the glioblastoma transcriptome has the potential to uncover a number of novel canonical/non-canonical relationships that could serve as future co-therapeutic targets. To investigate this, we employed RNAseq to compare the expression profiles of glioblastoma cell cultures transfected with either HK2-targeted or non-targeting negative-control siRNA, thereby identifying genes differentially expressed specifically following HK2KD. Gene ontology category enrichment (GOSeq, Enrichment map) and STRING protein-protein interaction analysis of genes identified to be differentially expressed post HK2 knockdown (HK2KD) highlighted potential non-canonical roles for HK2 in regulating inflammatory, immune and angiogenesis-related processes within the glioblastoma tumour microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325873 | GEO | 2026/05/04

REPOSITORIES: GEO

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Project description:Although metabolic benefits of glycolysis have been extensively described in tumor cells, the extra-metabolic functions linked to this energetic pathway in tumor growth and cell proliferation have not been clearly established yet. Recently, some key glycolytic enzymes, such as GAPDH and PKM2, were reported to regulate mRNA translation. Translational control of gene expression is considered as a critical effector in cancer biology, representing a highly promising area of research. Here, we report that Hexokinase 2 (HK2), a glucose kinase that catalyzes the first step of glycolysis at the outer mitochondrial membrane (OMM), is an RNA-binding protein (RBP) that regulates mRNA translation in melanoma cell lines. Polysome profiling experiments followed by RNA sequencing indicate that the translational regulation exerted by HK2 is partly independent of the metabolic status or the glycolytic pathway. We found that HK2 specifically regulates translation of the mRNA encoding SOX10, a transcription factor implicated in the regulation of tumor initiation, maintenance, and progression in melanoma. RNA-protein interaction assays, including crosslinking immunoprecipitation (CLIP), indicate that HK2 is an RBP whose interaction with RNA is independent of its enzymatic activity, its ability to bind glucose or its association with the OMM. HK2 directly interacts with the 5’ untranslated region (5’UTR) of the SOX10 mRNA through a stem-loop RNA secondary structure. Using RNA-protein proximity ligation assays and a fluorescence-based ribosome-bound mRNA mapping method (RIBOmap), we found that high glucose conditions, which promotes the release of HK2 from the OMM, induces an increase in HK2-SOX10 mRNA interaction and SOX10 mRNA translation in the cytoplasm. We further showed that HK2-dependent SOX10 mRNA translation is involved in melanoma cell proliferation and colony formation. Collectively, our data highlight a non-metabolic function of HK2 acting as an RBP and translation regulator.

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NOVEL HEXOKINASE-2 ASSOCIATED INFLAMMATORY PROCESSES IN THE GLIOBLASTOMA TUMOUR MICROENVIRONMENT

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