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

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-08-23 DOI:10.1038/s41388-025-03553-3

Junxiao Liu, Huayi Feng, Zhuang Xiong, Shouqing Cao, Tianwei Cai, Wenjie Wei, Wen Tao, Xu Zhang, Xin Ma, Xiubin Li

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引用次数: 0

Abstract

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.

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LGI3通过GEMIN6/AURKB轴促进tfe3重排肾细胞癌的进展。

转录因子结合IGHM增强子3-重排肾细胞癌（TFE3-RCC）具有侵袭性，治疗选择有限，预后差的特点。然而，TFE3融合蛋白在其肿瘤发生和进展中的下游靶点尚不清楚。在这里，我们证明了富含亮氨酸的重复LGI家族成员3 （LGI3）是TFE3融合蛋白的直接靶点。TFE3融合蛋白可以结合LGI3的启动子，激活LGI3的转录。重要的是，LGI3参与了TFE3-RCC的增殖、迁移和侵袭。在机制上，LGI3与gem核细胞器相关蛋白6 （GEMIN6）相互作用，并通过降低其泛素化来抑制其降解。GEMIN6上调可促进Aurora B激酶（AURKB） mRNA成熟，从而促进TFE3-RCC的进展。重要的是，靶向GEMIN6或AURKB的药物可显著抑制TFE3-RCC细胞和类器官的生长。在人TFE3-RCC组织中，LGI3高表达并与GEMIN6和AURKB正相关。总之，我们揭示了TFE3-RCC进展的新机制，并提供了潜在的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.