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Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma.
- Source :
-
Nature communications [Nat Commun] 2024 Oct 01; Vol. 15 (1), pp. 8506. Date of Electronic Publication: 2024 Oct 01. - Publication Year :
- 2024
-
Abstract
- Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Cell Line, Tumor
Animals
Mice
Tumor Microenvironment immunology
Gene Expression Regulation, Neoplastic
Tumor-Associated Macrophages metabolism
Tumor-Associated Macrophages immunology
Integrin beta1 metabolism
Integrin beta1 genetics
Glutarates metabolism
Mutation
YAP-Signaling Proteins metabolism
Glioblastoma genetics
Glioblastoma pathology
Glioblastoma metabolism
Glycolysis
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Isocitrate Dehydrogenase genetics
Isocitrate Dehydrogenase metabolism
Brain Neoplasms metabolism
Brain Neoplasms pathology
Brain Neoplasms genetics
Carcinogenesis genetics
beta-N-Acetylhexosaminidases metabolism
beta-N-Acetylhexosaminidases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39353936
- Full Text :
- https://doi.org/10.1038/s41467-024-52888-0