2. Academic Validation
  3. Targeting the C/EBPβ-PRAME-EZH2 complex modulates the Netrin-4/AKT axis to inhibit renal cancer tumorigenesis and metastasis

Targeting the C/EBPβ-PRAME-EZH2 complex modulates the Netrin-4/AKT axis to inhibit renal cancer tumorigenesis and metastasis

  • Cell Death Differ. 2026 Feb 12. doi: 10.1038/s41418-026-01683-z.
Li-Zhen Zhang # 1 2,  Zheng-Kun Zhang # 3 4,  Liang-Min Fu # 5,  Enyi Zhu # 6,  Chan Huang 7,  Han-Sen Lin 3,  Cheng-Peng Gui 3,  Gao-Wei Huang 3,  Zhen-Hua Chen 3,  Wei Chen 3,  Jian-Ping Guo 8,  Jin-Huan Wei 9,  Jun-Hang Luo 10 11
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 2 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 3 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 5 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6 The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, China.
  • 7 Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 8 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 9 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 10 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 11 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41680474 DOI: 10.1038/s41418-026-01683-z
Abstract

Cancer-testis antigens are considered clinically attractive targets for Cancer treatment, but their functions and mechanisms are not well elucidated. Here, based on comprehensive bioinformatics analyses, we identify PRAME, a nuclear cancer-testis antigen, as a potential regulator of metastasis in clear cell renal cell carcinoma (ccRCC). Subsequent RNA-Seq and functional studies illustrate that Netrin-4 (NTN4) is a major downstream effector of PRAME, involved in its oncogenic functions. Mechanism analyses reveal that PRAME interacts with the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) and the Histone Methyltransferase enhancer of zeste homolog 2 (EZH2) simultaneously, thereby forming a ternary complex. Subsequently, this complex co-occupies the NTN4 promoter locus, leading to increased trimethylation of histone H3 lysine 27 and epigenetic repression of NTN4 expression, resulting in Akt activation and promotion of ccRCC development. Interestingly, C/EBPβ is characterized to stimulate PRAME expression by binding to the PRAME promoter. Additionally, a cell-permeable peptide has been designed to disrupt the ternary complex and inhibit ccRCC progression in tumor cells and patient-derived xenografts. Thus, our findings not only provide new insights into the prominent role of PRAME in mediating C/EBPβ and EZH2 regulation of NTN4 and tumor metastasis, but also highlight a promising strategy for ccRCC therapy by targeting the C/EBPβ-PRAME-EZH2 complex.

Figures
Products