NONO-TFE3 Fusion Promotes Aerobic Glycolysis and Angiogenesis by Targeting HIF1A in NONO-TFE3 Translocation Renal Cell Carcinoma

Background: NONO-TFE3 translocation renal cell carcinoma (tRCC), one of the RCCs that are associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 tRCCs), involves an X chromosome inversion between NONO and TFE3 with the characteristics of endonuclear aggregation of NONO-TFE3 fusion protein. The oncogenic mechanisms of NONO-TFE3 fusion have not yet been fully elucidated. Objective: This study aimed at investigating the mechanism of NONO-TFE3 fusion regulating HIF1A as well as the role of HIF-1 alpha in the progression of NONO-TFE3 tRCC under hypoxia. Methods: Immunohistochemistry and Western Blotting assays were performed to profile HIF-1 alpha expression in renal clear cell carcinoma (ccRCC) or in Xp11.2 tRCC. Chromatin immunoprecipitation (ChIP), a luciferase reporter assay, and real-time quantitative PCR (RT-qPCR) were used to evaluate the regulation of HIF1A expression by NONO-TFE3 fusion. Then, the flow cytometry analysis, tube formation assays, and cell migration assays were used as well as glucose or lactic acid levels were measured to establish the impact of HIF-1 alpha on the progression of NONO-TFE3 tRCC. Besides, the effect of HIF-1 alpha inhibitor (PX-478) on UOK109 cells was analyzed. Results: We found that HIF1A was the target gene of NONO-TFE3 fusion. In UOK109 cells, which were isolated from NONO-TFE3 tRCC samples, NONO-TFE3 fusion promoted aerobic glycolysis and angiogenesis by up-regulating the expression of HIF-1 alpha under hypoxia. Furthermore, the inhibition of HIF-1 alpha mediated by PX-478 suppressed the development of NONO-TFE3 tRCC under hypoxia. Conclusion: HIF-1 alpha is a potential target for therapy of NONO-TFE3 tRCC under hypoxia.

Automated summary

The study revealed that HIF1A is a target gene of NONO-TFE3 fusion, promoting aerobic glycolysis and angiogenesis in NONO-TFE3 tRCC under hypoxia. Inhibition of HIF-1 alpha using PX-478 suppressed the progression of NONO-TFE3 tRCC under hypoxia, suggesting HIF-1 alpha as a potential therapeutic target for this type of cancer.