Work

TFE3 fusion proteins promoted the progression of Xp11.2 translocation renal cell carcinoma through post-translational modification of PDL1 by upregulating CCND1/Cyclin D1

Year: 2025

Type: article

Abstract: BACKGROUND: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a very rare and aggressiveness malignancy with poor outcome. Previous studies suggested that programmed cell death protein-1 ligand 1 (PDL1) was characterized with high mRNA and low protein in Xp11.2 tRCC, however, the potential mechanism is still blurry. METHODS: Immunohistochemistry was conducted to verify Cyclin D1 and PDL1 expression in Xp11.2 tRCC. ChIP and dual-luciferase reporter gene assay were applied to evaluate transcriptional-regulation of TFE3 fusion proteins on CCND1/Cyclin D1 and NR1D1, we used RNA-seq to detect the regulation role of NR1D1 on CCND1/Cyclin D1, half-life experiment and autophagy flux were employed to demonstrate Cyclin D1-CDK4 speeded PDL1 degradation. RESULTS: Here, we demonstrated that CCND1/Cyclin D1 was not only a direct target gene for positive regulation of TFE3 fusion proteins, but also up-regulated by nuclear receptor subfamily 1 group D member 1 (NR1D1) which was positively transcriptional regulation of TFE3 fusion proteins. Besides, TFE3 fusion proteins reduced the degradation of Cyclin D1 by activating the AKT/mTOR pathway. As a result, the high-expression of CCND1/Cyclin D1 mediated degradation of PDL1 protein through ubiquitin-proteasome system and autophagy pathway. CONCLUSION: This research found that CCND1/Cyclin D1 was upregulated in Xp11.2 tRCC through three mechanisms, high-expression CCND1/Cyclin D1 inducing PDL1 degradation. Overall, the study provided a theoretical basis for sequentially using CDK4 inhibitors and anti-PDL1 for Xp11.2 tRCC treatment. CLINICAL TRIAL NUMBER: Not applicable.

Source: Cellular Oncology

DOI: 10.1007/s13402-025-01125-x