RNA-mediated condensation of TFE3 oncofusions facilitates transcriptional hub formation to promote translocation renal cell carcinoma

Abstract

Abstract Transcription factor E3 (TFE3) oncofusions are frequently detected in the Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC), a rare pediatric renal cancer with limited treatment options. The mechanisms by which TFE3 oncofusions promote tRCC malignancy remain inadequately defined. Here, we demonstrate that the RNA-binding capability conferred by TFE3 fusion partners drives the formation of TFE3 condensates. This further enables TFE3 oncofusions to co-condensate with RNA polymerase II (RNAPII) and other RNA-binding proteins, such as paraspeckle component 1 (PSPC1), ultimately driving the formation of transcriptional hubs to promote pro-oncogenic transcription. Dissolution of oncofusion condensates through nanobody-based chemogenetic manipulation effectively curtails tRCC cell growth both in vitro and in vivo, suggesting the therapeutic potential for targeting oncofusion condensation in tRCC. Collectively, our study establishes the causal role of RNA and RNA-binding proteins in facilitating oncofusion condensation to promote renal cancer progression.