Abstract
Abnormal nuclear structure caused by dysregulation of skeletal proteins is a common phenomenon in tumour cells. However, how skeletal proteins promote tumorigenesis remains uncovered. Here, we revealed the mechanism by which skeletal protein Emerin (EMD) promoted glucose metabolism to induce lung adenocarcinoma (LUAD). Firstly, we identified that EMD was highly expressed and promoted the malignant phenotypes in LUAD. The high expression of EMD might be due to its low level of ubiquitination. Additionally, the ISGylation at lysine 37 of EMD inhibited lysine 36 ubiquitination and upregulated EMD stability. We further explored that EMD could inhibit aerobic oxidation and stimulate glycolysis. Mechanistically, via its β-catenin interaction domain, EMD bound with PDHA, stimulated serine 293 and 300 phosphorylation and inhibited PDHA expression, facilitated glycolysis of glucose that should enter the aerobic oxidation pathway, and EMD ISGylation was essential for EMD-PDHA interaction. In clinical LUAD specimens, EMD was negatively associated with PDHA, while positively associated with EMD ISGylation, tumour stage and diameter. In LUAD with higher glucose level, EMD expression and ISGylation were higher. Collectively, EMD was a stimulator for LUAD by inhibiting aerobic oxidation via interacting with PDHA. Restricting cancer-promoting role of EMD might be helpful for LUAD treatment.
Keywords:
ISG15; glucose metabolism; glycolysis; proteasome; skeletal proteins; ubiquitination.