LGI3 promotes the progression of TFE3-rearranged renal cell carcinoma through GEMIN6/AURKB axis.

Transcription factor binding to IGHM enhancer 3-rearranged renal cell carcinoma (TFE3-RCC) is characterized by its aggressive nature, limited treatment options, and poor prognosis. However, the downstream targets of TFE3 fusion protein responsible for its tumorigenesis and progression remain unclear. Here, we demonstrated that leucine-rich repeat LGI family member 3 (LGI3) is a direct target of TFE3 fusion protein. TFE3 fusion protein can bind to the promoter of LGI3 and then activate its transcription. Importantly, LGI3 contributes to the proliferation, migration, and invasion of TFE3-RCC. Mechanistically, LGI3 interacts with gem nuclear organelle-associated protein 6 (GEMIN6) and inhibits its degradation via decreasing its ubiquitination. GEMIN6 upregulation promotes the mRNA maturation of Aurora B kinase (AURKB), thereby promoting the progression of TFE3-RCC. Importantly, drugs targeting GEMIN6 or AURKB significantly suppressed the growth of TFE3-RCC cells and organoids. In human TFE3-RCC tissues, LGI3 is highly expressed and positively correlated with GEMIN6 and AURKB. Overall, we revealed a novel mechanism underlying the progression of TFE3-RCC and provided potential new therapeutic targets.