2. Academic Validation
  3. GNL3 Orchestrates AR Transcriptional Programs to Drive Castration-Resistant Prostate Cancer and Immune Evasion

GNL3 Orchestrates AR Transcriptional Programs to Drive Castration-Resistant Prostate Cancer and Immune Evasion

  • Adv Sci (Weinh). 2026 May;13(26):e16411. doi: 10.1002/advs.202516411.
Cuiting Zhang 1 2 3 4,  Tin Long Cheong 1 2 3 4,  Nitin Narwade 1 2 3 4,  Dandan Dong 5,  Mokan Deng 1 2 3 4,  Zhengqiang Miao 6,  Zhaoqiang Ding 1 2 3 4,  Wenchao Li 7,  Kate Man Kei Lei 1 2 3 4 8 9,  Gong-Hong Wei 5 10,  Terence Chuen Wai Poon 1 2 3 4 8 9,  Chu-Xia Deng 1 2 3 4 11,  Edwin Cheung 1 2 3 4 11
Affiliations

Affiliations

  • 1 Cancer Centre, University of Macau, Taipa, Macau SAR, China.
  • 2 Centre for Precision Medicine Research and Training, University of Macau, Taipa, Macau SAR, China.
  • 3 MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
  • 4 Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
  • 5 Fudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 6 Genomics, Bioinformatics & Single Cell Core, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
  • 7 Department of Urology, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China.
  • 8 Pilot Laboratory, University of Macau, Taipa, Macau SAR, China.
  • 9 Institute of Translational Medicine, University of Macau, Taipa, Macau SAR, China.
  • 10 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China.
  • 11 Zhuhai UM Science & Technology Research Institute (ZUMRI), Hengqin, Zhuhai, China.
PMID: 41772945 DOI: 10.1002/advs.202516411
Abstract

Androgen Receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate Cancer (CRPC), yet the mechanism remains incompletely understood. Through proteomic profiling of CRPC and primary PCa cells, we identify G Protein Nucleolar 3 (GNL3) as a novel AR coregulator. GNL3 physically interacts with AR, enhances its chromatin occupancy, and directly coactivates transcriptional programs that promote cell proliferation, including NEK2 and CDC20. Concurrently, GNL3 functions as a corepressor of immune-responsive genes such as CXCL10 and TAP1 via class I histone deacetylases (HDACs), thereby facilitating CD8+ T cell elimination and establishing an immunosuppressive tumor microenvironment. GNL3 expression and AR-GNL3 complex formation progressively increase from normal prostate to CRPC and correlate with poor clinical outcomes. Functionally, GNL3 knockdown sensitizes CRPC cells to AR antagonists and impairs tumor growth and metastasis. Furthermore, we demonstrate that combinatorial inhibition of NEK2, class I HDACs, and AR signaling can be a potential therapeutic strategy for CRPC. Overall, these findings establish GNL3 as a dual-function AR coregulator and therapeutic target, providing mechanistic insights into transcriptional regulation and immune evasion in advanced PCa.

Keywords

AR coregulator; GNL3; castration‐resistant prostate cancer; immunosuppression.

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