TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer in translocation renal cell carcinoma

被引：0

作者：

So, Choon Leng ^{[1
]}

Lee, Ye Jin ^{[1
]}

Vokshi, Bujamin H. ^{[2
]}

Chen, Wanlu ^{[2
,3
]}

Huang, Binglin ^{[1
]}

De Sousa, Emily ^{[1
]}

Gao, Yangzhenyu

Portuallo, Marie Elena ^{[1
]}

Begum, Sumaiya ^{[1
]}

Jagirdar, Kasturee ^{[1
]}

Linehan, W. Marston ^{[4
]}

Rebecca, Vito W. ^{[1
,2
]}

Ji, Hongkai ^{[3
]}

Toska, Eneda ^{[1
,2
]}

Cai, Danfeng ^{[1
,2
,5
]}

机构：

[1] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA

[2] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[3] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA

[4] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA

[5] Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA

来源：

CELL REPORTS | 2025年 / 44卷 / 04期

关键词：

RNA-POLYMERASE-II; PHASE-SEPARATION; GENE; ELEMENTS; TARGET; DOMAIN; ESTABLISHMENT; AGGREGATION; MECHANISMS; INHIBITION;

D O I：

10.1016/j.celrep.2025.115539

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：29

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