TRIM46 activates AKT/HK2 signaling by modifying PHLPP2 ubiquitylation to promote glycolysis and chemoresistance of lung cancer cells.

The incidence of lung cancer is increasing worldwide. Although great progress in lung cancer treatment has been made, the clinical outcome is still unsatisfactory. Tripartite motif (TRIM)-containing proteins has been shown to be closely related to tumor progression. However, the function of TRIM46 in lung cancer is largely unknown. Here, TRIM46 amplification was found in lung adenocarcinoma (LUAD) tissues and TRIM46 amplification was significantly associated with a poor survival rate. Overexpression of wild type TRIM46 increased the proliferation of LUAD cells and glycolysis, promoted xenografts growth, and enhanced cisplatin (DDP) resistance of LUAD cells via increased ubiquitination of pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) and upregulation of p-AKT. In contrast, overexpression of RING-mutant TRIM46 did not show any effects, suggesting the function of TRIM46 was dependent on the E3 ligase activity. Furthermore, we found that TRIM46 promoted LUAD cell proliferation and DDP resistance by enhancing glycolysis. PHLPP2 overexpression reversed the effects of TRIM46 overexpression. Amplification of TRIM46 also promoted LUAD growth and enhanced its DDP resistance in a patient-derived xenograft (PDX) model. In conclusion, our data highlight the importance of TRIM46/PHLPP2/AKT signaling in lung cancer and provide new insights into therapeutic strategies for lung cancer.