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Perturbing RNA-mediated condensation of TFE3 oncofusion proteins to suppress renal cell carcinoma growth

ABSTRACT: Chromosomal rearrangement-mediated oncofusion proteins are major oncogenic drivers, with high prevalence in pediatric cancers, which often have a poor prognosis. Liquid-like condensate formation has been reported in many oncofusion proteins, supporting their oncogenic signaling and transcriptional regulation. In this study, we report that RNA-mediated nuclear condensate formation plays an essential role in supporting the oncogenic transcription of TFE3 oncofusion proteins in MiT family translocation renal cell carcinoma (tRCC), which often occurs in children and adolescents and is considered an orphan disease in RCC lacking effective treatment. The RNA binding features in the fusion partners of transcription factor E3 (TFE3) support the nuclear condensate formation of TFE3 oncofusion proteins on the chromatin, thereby enabling RNA polymerase II (RNAPII) and other RNA binding proteins, e.g., paraspeckle component 1 (PSPC1), to co-condensate and form a transcriptional hub to support oncogenic transcription in tRCC. Perturbing TFE3 oncofusion condensate formation using a nanobody fused with maltose-binding protein (MBP) approach significantly suppresses tRCC cell growth in vitro and in vivo. In summary, our data highlight the pivotal role of RNA and RNA binding proteins in supporting the liquid-like condensate formation of oncofusion proteins and in promoting oncogenic transcription.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Rongjie Zhao

LAB HEAD: Yun Nancy Huang

PROVIDER: PXD056977 | Pride | 2025-09-05

REPOSITORIES: Pride

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