USF2 regulates the JAK2/STAT3 pathway through PEX3-mediated SLC25A17 upregulation to affect lipid metabolism and promote the progression of lung adenocarcinoma

Abstract

Upstream Stimulator Factor 2 (USF2) has been identified as an oncogenic factor in various types of cancer; however, its precise biological function and underlying molecular mechanisms in the pathogenesis of lung cancer remain to be fully elucidated. In this study, we found that USF2 was markedly upregulated in lung adenocarcinoma (LUAD) tissues and cells. Knockdown of USF2 inhibits A549 cell proliferation and invasion and induces cell apoptosis. Overexpression of USF2 promotes abnormal lipid metabolism in A549 cells, as evidenced by elevated levels of triglycerides, cholesterol, and free fatty acids, upregulated fatty acid synthase levels, and downregulated acyl-CoA oxidase 1 levels. Mechanistically, USF2 directly binds to the promoter of Peroxisome biogenesis factor 3 (PEX3) to drive its transcriptional activation. Upregulated PEX3 promotes abnormal lipid metabolism in LUAD cells by interacting with solute carrier family 25 member 17 (SLC25A17) to upregulate its protein levels. Knockdown of PEX3 reverses the effects of USF2 overexpression on A549 cells. Additionally, SLC25A17 overexpression exacerbates lipid accumulation in A549 cells by activating the janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, while AG490, a JAK2 inhibitor, eliminates this effect. Finally, a xenograft tumor model was established by subcutaneously injecting A549 cells transfected with sh-USF2 lentiviral vectors into nude mice. Results showed that USF2 knockdown inhibits abnormal lipid metabolism and tumor growth in xenografted mice. In conclusion, our study demonstrates that USF2 overexpression enhances SLC25A17-mediated JAK2/STAT3 signaling by promoting PEX3 transcriptional activation, thereby exacerbating abnormal lipid metabolism in A549 cells and accelerating LUAD progression.