Starvation-induced HBP metabolic reprogramming and STAM2 O-GlcNAcylation facilitate bladder cancer metastasis.

IF 3.9 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Scientific Reports Pub Date : 2025-03-12 DOI:10.1038/s41598-025-92579-4

Zhenwei Feng, Yuhua Mei, Haonan Chen, Li Li, Tian Jin, Xinyuan Li, Xin Gou, Yong Chen

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Abstract

Metabolic reprogramming and epigenetic alternations are implicated in tumor progression and metastasis, but the metabolic and epigenetic mechanisms underlying lymphatic and distant metastasis of bladder cancer (BCa) remain poorly understood. In this study, we provide the first evidence that glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the crucial rate-limiting switch of the hexosamine biosynthesis pathway (HBP), is considerably upregulated in the nutrient-scarce microenvironment and causes a high O-GlcNAcylation of signal transducing adaptor molecule 2 (STAM2), further facilitating lymphatic and distant metastasis of BCa. Inhibition of GFAT1 and O-GlcNAcylation impairs STAM2-induced metastasis. Mechanistically, O-GlcNAcylation of STAM2 at serine 375 augments protein stability by inhibiting proteasome degradation and ubiquitination. In addition, STAM2 O-GlcNAcylation facilitates Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) phosphorylation, thus activating the epithelial‒mesenchymal transition. In summary, these results reveal a novel metabolic and epigenetic link mediating tumor metastasis, and indicate that targeting GFAT1 and STAM2 O-GlcNAcylation may serve as a promising treatment strategy for BCa progression.

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饥饿诱导的HBP代谢重编程和STAM2 o - glcn酰化促进膀胱癌转移。

代谢重编程和表观遗传改变与肿瘤进展和转移有关，但膀胱癌（BCa）淋巴转移和远处转移的代谢和表观遗传机制尚不清楚。在这项研究中，我们提供了第一个证据，证明谷氨酰胺-果糖-6-磷酸转氨酶1 （GFAT1）是己糖胺生物合成途径（HBP）的关键限速开关，在营养匮乏的微环境中显著上调，并导致信号转导受体分子2 （STAM2）的高o - glcn酰化，进一步促进BCa的淋巴和远处转移。抑制GFAT1和o - glcn酰化会损害stam2诱导的转移。机制上，STAM2丝氨酸375处的o - glcn酰化通过抑制蛋白酶体降解和泛素化来增强蛋白质的稳定性。此外，STAM2 o - glcnac酰化促进了Janus kinase 2 （JAK2）和转录信号换能器和激活因子（STAT3）的磷酸化，从而激活了上皮-间质转化。总之，这些结果揭示了介导肿瘤转移的一种新的代谢和表观遗传联系，并表明靶向GFAT1和STAM2 o - glcn酰化可能是一种有希望的治疗BCa进展的策略。

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来源期刊

Scientific Reports Natural Science Disciplines-

CiteScore

7.50

自引率

4.30%

发文量

19567

审稿时长

3.9 months

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