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Hypoxia conduces the glioma progression by inducing M2 macrophage polarization via elevating TNFSF9 level in a histone-lactylation-dependent manner.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2024 Aug 01; Vol. 327 (2), pp. C487-C504. Date of Electronic Publication: 2024 Jul 16. - Publication Year :
- 2024
-
Abstract
- Hypoxia is a critical factor contributing to a poor prognosis and challenging glioma therapy. Previous studies have indicated that hypoxia drives M2 polarization of macrophages and promotes cancer progression in various solid tumors. However, the more complex and diverse mechanisms underlying this process remain to be elucidated. Here, we aimed to examine the functions of hypoxia in gliomas and preliminarily investigate the underlying mechanisms of M2 macrophage polarization caused by hypoxia. We found that hypoxia significantly enhances the malignant phenotypes of U87 and U251 cells by regulating glycolysis. In addition, hypoxia mediated accumulation of the glycolysis product [lactic acid (LA)], which is subsequently absorbed by macrophages to induce its M2 polarization, and this process is reverted by both the glycolysis inhibitor and silenced monocarboxylate transporter (MCT-1) in macrophages, indicating that M2 macrophage polarization is associated with the promotion of glycolysis by hypoxia. Interestingly, we also found that hypoxia mediated LA accumulation in glioma cells upon uptake by macrophages upregulates H3K18La expression and promotes tumor necrosis factor superfamily member 9 (TNFSF9) expression in a histone-lactylation-dependent manner based on the results of chromatin immunoprecipitation sequencing (ChIP seq) enrichment analysis. Subsequent in vitro and in vivo experiments further indicated that TNFSF9 facilitated glioma progression. Mechanistically, hypoxia-mediated LA accumulation in glioma cells is taken up by macrophages and then induces its M2 macrophage polarization by regulating TNFSF9 expression via MCT-1/H3K18La signaling, thus facilitating the malignant progression of gliomas. NEW & NOTEWORTHY Our study revealed that hypoxia induces the production of LA accumulation through glycolysis in glioma cells, which is subsequently absorbed by macrophages and leads to its M2 polarization via the MCT-1/H3K18La/TNFSF9 axis, ultimately significantly promoting the malignant progression of glioma cells. These findings are novel and noteworthy as they provide insights into the connection between energy metabolism and epigenetics in gliomas.
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Glycolysis
Disease Progression
Monocarboxylic Acid Transporters metabolism
Monocarboxylic Acid Transporters genetics
Brain Neoplasms pathology
Brain Neoplasms metabolism
Brain Neoplasms genetics
Mice, Nude
Cell Hypoxia
Lactic Acid metabolism
Gene Expression Regulation, Neoplastic
Macrophage Activation
Glioma pathology
Glioma metabolism
Glioma genetics
Macrophages metabolism
Macrophages pathology
Histones metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1563
- Volume :
- 327
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 39010835
- Full Text :
- https://doi.org/10.1152/ajpcell.00124.2024