2023 World Conference on Lung Cancer (Posters)-P1.02. Glucose Deprivation Promotes Pseudo-Hypoxia and De-differentiation in Lung Adenocarcinoma

P1.02. Glucose Deprivation Promotes Pseudo-Hypoxia and De-differentiation in Lung Adenocarcinoma - PDF(Slides)

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Glucose deprivation in lung adenocarcinoma (LUAD) cells leads to tumor cell de-differentiation and a more aggressive phenotype, according to a study conducted by researchers at the University of California Los Angeles and the University of Salerno. The researchers discovered that glucose restriction resulted in a reduction in alpha-ketoglutarate (αKG), which impaired the activity of αKG-dependent histone demethylases and led to histone hypermethylation. This caused the cancer cells to undergo de-differentiation and adopt a more aggressive phenotype. Further investigation revealed that this de-differentiated state was dependent on the activity of EZH2, a histone methyltransferase, which inhibited the expression of Prolyl-4-hydroxylase domain 3 (PHD3) and increased the levels of hypoxia inducible factor 1α (HIF1α). HIF1α activation triggered epithelial to mesenchymal transition (EMT) and increased the aggressiveness of the cancer cells. The researchers also identified an HIF1α-dependent transcriptional signature that had prognostic significance in human LUAD. In addition, they found that inhibition of EZH2 reduced tumor burden in mouse models of LUAD. The study highlights the role of glucose metabolism in cancer cell differentiation and identifies potential targets for metabolic therapies targeting glucose uptake and glycolysis. These findings provide insights into the adaptive responses of cancer cells to glucose restriction and may have implications for the development of new treatment strategies for LUAD.

Asset Subtitle

Claudio Scafoglio

Meta Tag

Speaker Claudio Scafoglio

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

glucose deprivation

lung adenocarcinoma

tumor cell de-differentiation

aggressive phenotype

alpha-ketoglutarate

histone hypermethylation

EZH2

HIF1α

epithelial to mesenchymal transition

metabolic therapies