Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
Nat Commun. 2024 Oct 1;15(1):8506. doi: 10.1038/s41467-024-52888-0.
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.
肿瘤细胞的糖酵解代谢重编程受多种因素调控，包括肿瘤内在变异（如异柠檬酸脱氢酶 1（IDH1）状态）和非肿瘤性微环境成分（如肿瘤相关巨噬细胞（TAMs））。然而，其具体机制仍不清楚。在这里，我们发现β-己糖胺酶 B（HEXB）是胶质母细胞瘤（GBM）中糖酵解的关键调节因子。HEXB 通过细胞间作用调节 TAMs，促进 GBM 细胞中的糖酵解，同时内在增强癌细胞的糖酵解。从机制上讲，HEXB 通过激活 ITGB1/ILK/YAP1 来增加肿瘤 HIF1α 蛋白的稳定性；随后，HIF1α 在 GBM 细胞中促进 HEXB 和多个糖酵解基因的转录。在 GBM 的临床前模型中，对 HEXB 的遗传消融和药物抑制会产生显著的治疗效果，而靶向 HEXB 不会导致 IDH1 突变型胶质瘤显著减少，抑制 IDH1 突变衍生的 2-羟戊二酸（2-HG）则会显著恢复胶质瘤细胞中 HEXB 的表达。我们的工作强调了 GBM 中由 HEXB 驱动的 TAMs 相关糖酵解促进网络，并为开发针对该网络的更有效的治疗方法提供了线索。
