TFE3 Fusion Oncoproteins' Role in Renal Cell Carcinoma

TFE3 Fusion Oncoproteins and Their Impact on Cancer Progression

TFE3 is a member of the microphthalmia-associated transcription factor family, which plays a crucial role in regulating gene expression related to cell growth and differentiation. In tRCC, TFE3 is commonly fused with genes such as NONO or SFPQ, leading to the formation of TFE3 fusion oncoproteins. These fusions create a hybrid protein that retains the transcriptional activation domain of TFE3 while acquiring new functionalities from the fusion partner. As a result, TFE3 fusion oncoproteins exhibit enhanced transcriptional activity, driving oncogenic pathways that promote cell proliferation and migration (So et al., 2025).

Research has shown that TFE3 fusion oncoproteins form liquid-like condensates within cells, which are crucial for their transcriptional activities. These condensates allow for the concentration of transcriptional machinery near target genes, facilitating a more efficient expression of oncogenic genes. The coiled-coil domains (CCDs) of NONO and SFPQ are particularly significant for this condensate formation, which prolongs the binding time of TFE3 to chromatin, thereby enhancing transcription (So et al., 2025).

Mechanisms of TFE3 Condensate Formation in Tumor Cells

The formation of TFE3 condensates is driven by weak, multivalent interactions among macromolecules, a characteristic feature of biomolecular condensates. TFE3 fusion oncoproteins utilize their CCDs to mediate these interactions, promoting phase separation and the formation of distinct nuclear foci. Studies have demonstrated that TFE3 fusion oncoproteins localize to these condensates, which co-localize with active transcription markers, indicating their involvement in driving transcriptional programs associated with tRCC (So et al., 2025).

The role of condensates in transcriptional regulation is further underscored by the fact that TFE3 FOs can bind to new chromatin regions, altering chromatin accessibility and forming new enhancers and super-enhancers at pro-growth gene loci. This remodeling of the chromatin landscape is essential for the transcriptional output necessary for tumor progression (So et al., 2025).

Role of Aryl Hydrocarbon Receptor in TFE3 Oncogenic Activity

The aryl hydrocarbon receptor (AhR) has been implicated in mediating the effects of TFE3 fusion oncoproteins. AhR is a ligand-activated transcription factor that regulates genes involved in xenobiotic metabolism and cellular signaling pathways. Studies indicate that TFE3 fusion oncoproteins enhance the expression of AhR target genes, which can contribute to the oncogenic processes in tRCC. Inhibition of AhR has been shown to disrupt the transcriptional activity of TFE3 FOs, highlighting its potential as a therapeutic target in tRCC (So et al., 2025).

Therapeutic Strategies Targeting TFE3 Condensates in tRCC

Given the critical role of TFE3 fusion oncoproteins in tRCC, innovative therapeutic strategies are being explored. Targeting the condensate formation process represents a promising avenue. Such strategies could involve the use of small molecules or peptides that disrupt the interactions necessary for condensate formation, thereby reducing the transcriptional activity of TFE3 FOs.

Moreover, targeting downstream signaling pathways regulated by TFE3 FOs, including those involving AhR, may provide an additional layer of therapeutic intervention. By inhibiting these pathways, it may be possible to halt the progression of tRCC and improve patient outcomes. Clinical trials are needed to validate the efficacy of these strategies and identify optimal combinations that can effectively target TFE3-mediated oncogenesis (So et al., 2025).

Implications of TFE3 Gene Fusion for Future Cancer Treatments

The identification of TFE3 fusion oncoproteins as pivotal drivers of tRCC opens new avenues for targeted therapy. Understanding the mechanisms by which these oncoproteins drive transcriptional reprogramming provides a foundation for developing innovative treatment strategies. As research progresses, it is anticipated that therapies targeting TFE3 fusion oncoproteins will play a significant role in the management of tRCC, particularly in patients with advanced disease.

Table: Overview of TFE3 Fusion Oncoproteins in tRCC

Fusion Partner	Frequency	Mechanism of Action	Potential Therapeutic Target
NONO	30-40%	Forms condensates, enhances transcriptional activity	Disruption of condensate formation
SFPQ	30-40%	Mediates recruitment of transcriptional machinery	Inhibition of AhR pathway
PRCC	Rare	Alters chromatin accessibility, promotes tumor growth	Targeting downstream signaling
ASPSCR1	Rare	Similar to others, alters gene expression	Combination therapies

FAQ

What is TFE3 Fusion Oncoprotein?
TFE3 fusion oncoproteins are hybrid proteins resulting from chromosomal rearrangements that contribute to the development of translocation renal cell carcinoma (tRCC). They typically involve the fusion of the TFE3 gene with other genes, leading to altered gene expression and tumorigenesis.

How do TFE3 Fusion Oncoproteins affect cancer progression?
TFE3 fusion oncoproteins promote cancer progression by enhancing transcriptional activity, altering chromatin accessibility, and facilitating the formation of new enhancers at genes associated with cell growth.

What role does the Aryl Hydrocarbon Receptor (AhR) play in TFE3 oncogenic activity?
AhR is involved in mediating the transcriptional effects of TFE3 fusion oncoproteins, and its inhibition can disrupt the oncogenic effects of TFE3 FOs, making it a potential target for therapeutic intervention.

What therapeutic strategies are being explored for targeting TFE3 fusion oncoproteins?
Innovative strategies include disrupting condensate formation of TFE3 FOs and targeting downstream signaling pathways, particularly those regulated by AhR.

What are the future implications of TFE3 gene fusion for cancer treatment?
The understanding of TFE3 fusion oncoproteins as drivers of tRCC provides a basis for developing targeted therapies, which may significantly improve treatment outcomes for patients with this aggressive form of cancer.

References

So, C. L., Lee, Y. J., Vokshi, B. H., Chen, W., Huang, B., De Sousa, E., Gao, Y., Portuallo, M. E., Begum, S., Jagirdar, K., Linehan, W. M., & Cai, D. (2025). TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma. Cell Reports, 31(9), 115539. https://doi.org/10.1016/j.celrep.2025.115539
Zhou, Y., Feng, Y., Zhao, Y., Wu, Y., Li, M., Yang, X., & Chen, X. (2025). Oral 7,8‐Dihydroxyflavone Protects Retinal Ganglion Cells by Modulating the Gut‐Retina Axis and Inhibiting Ferroptosis via the Indoleacrylic Acid‐AhR‐ALDH1A3‐FSP1 Pathway. CNS Neuroscience & Therapeutics, 31(5)
Fu, J., Jin, Z., & Li, J. (2025). Anticoagulant effects, substance basis, and quality assessment approach of Aspongopus chinensis Dallas. PLoS One, 15(5), e0320165. https://doi.org/10.1371/journal.pone.0320165