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The CBL-LSD1-CXCL8 axis regulates methionine metabolism in glioma
Jie Chang1, Lude Wang1, Xi Zhou2
1Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, China.
Abstract:
Gliomas are the most frequent type of brain tumors, with a high mortality rate and a lack of efficient targeted therapy. Methionine is an essential amino acid, and restriction of methionine in the diet has been found to prevent metabolic diseases and aging, inhibit cancer growth and improve cancer treatment. However, mechanisms of action by which methionine metabolism affects gliomas remain largely unclear. The present study found that methionine starvation of glioma cells significantly increased the expression of CXCL8. Mechanistically, E3 ubiquitin ligase was found to mediate the ubiquitinated degradation of the histone demethylase LSD1 via CBL, reducing LSD1 protein stability and, enhancing H3K4me1 modification of the CXCL8 gene. CXCL8 was found to be involved in regulating the reprogramming of glycerophospholipid metabolism, enabling it to respond to a methionine-deprived environment. CXCL8 expression was significantly higher in glioma than in normal brain tissue samples, with elevated CXCL8 being associated with poor prognosis. In summary, CBL-mediated degradation of LSD1 acts as an anti-braking system and serves as a quick adaptive mechanism for re-remodeling epigenetic modifications. This, in turn, promotes cell proliferation, even in a methionine-restricted environment. Taken together, these findings indicate that the CBL/LSD1/CXCL8 axis is a novel mechanistic connection linking between methionine metabolism, histone methylation and glycerophospholipid reprogramming in the tumor microenvironment.
Insights
Methionine restriction in gliomas increases CXCL8 via CBL-mediated LSD1 degradation, promoting cell proliferation. This axis links methionine metabolism, histone methylation, and lipid reprogramming in brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Gliomas are aggressive brain tumors with poor prognosis and limited targeted therapies.
- Methionine restriction impacts aging and cancer, but its role in glioma is unclear.
- Understanding methionine metabolism's influence on glioma is crucial for developing new treatments.
Purpose of the Study:
- To elucidate the mechanisms by which methionine metabolism affects glioma.
- To identify key molecular players linking methionine metabolism to glioma progression.
- To explore the therapeutic potential of targeting this pathway.
Main Methods:
- Investigated the effect of methionine starvation on glioma cells.
- Utilized techniques to study protein degradation, ubiquitination, and histone modification.
- Analyzed gene expression (CXCL8) and protein levels (LSD1, CBL).
- Examined clinical glioma samples for CXCL8 expression.
Main Results:
- Methionine starvation upregulated CXCL8 expression in glioma cells.
- CBL-mediated ubiquitination and degradation of LSD1 was identified as a key mechanism.
- This process led to increased H3K4me1 modification of the CXCL8 gene.
- CXCL8 reprogramming of glycerophospholipid metabolism aids glioma adaptation to methionine deprivation.
- Elevated CXCL8 levels in glioma tissues correlate with poor patient prognosis.
Conclusions:
- The CBL/LSD1/CXCL8 axis represents a novel link between methionine metabolism, epigenetic modification, and metabolic reprogramming in gliomas.
- This pathway facilitates glioma cell proliferation under methionine-restricted conditions.
- Targeting the CBL/LSD1/CXCL8 axis may offer a new therapeutic strategy for glioma treatment.
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