TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma
Choon Leng So,
Ye Jin Lee,
Bujamin H. Vokshi,
Wanlu Chen,
Binglin Huang,
Emily De Sousa,
Yangzhenyu Gao,
Marie Elena Portuallo,
Sumaiya Begum,
Kasturee Jagirdar,
W. Marston Linehan,
Vito W. Rebecca,
Hongkai Ji,
Eneda Toska,
Danfeng Cai
Affiliations
Choon Leng So
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Ye Jin Lee
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Bujamin H. Vokshi
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Wanlu Chen
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Binglin Huang
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Emily De Sousa
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Yangzhenyu Gao
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Marie Elena Portuallo
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Sumaiya Begum
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Kasturee Jagirdar
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
W. Marston Linehan
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
Vito W. Rebecca
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Hongkai Ji
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Eneda Toska
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Danfeng Cai
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. It is primarily driven by fusion oncoproteins (FOs), yet their role in oncogenesis is not fully understood. Here, we investigate TFE3 fusions in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3. We demonstrate that TFE3 FOs form liquid-like condensates with increased transcriptional activity, localizing to TFE3 target genes and promoting cell proliferation and migration. The coiled-coil domains (CCDs) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs’ chromatin binding time and enhancing transcription. Compared with wild-type TFE3, TFE3 FOs bind to new chromatin regions, alter chromatin accessibility, and form new enhancers and super-enhancers at pro-growth gene loci. Disruption of condensate formation via CCD modification abolishes these genome-wide changes. Altogether, our integrated analyses underscore the critical functions of TFE3 FO condensates in driving tumor cell growth, providing key insights for future therapeutic strategies.
