The CBL-LSD1-CXCL8 axis regulates methionine metabolism in glioma

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.