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GNL3 Orchestrates AR Transcriptional Programs to Drive Castration-Resistant Prostate Cancer and Immune Evasion
Cuiting Zhang1,2,3,4, Tin Long Cheong1,2,3,4, Nitin Narwade1,2,3,4
1Cancer Centre, University of Macau, Taipa, Macau SAR, China.
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.
Insights
G Protein Nucleolar 3 (GNL3) is a novel androgen receptor (AR) coregulator in castration-resistant prostate cancer (CRPC). GNL3 drives tumor growth and immune evasion, making it a potential therapeutic target for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC).
- Mechanisms of AR signaling in CRPC are not fully understood.
- Identifying novel AR coregulators is crucial for understanding CRPC progression.
Purpose of the Study:
- To identify novel AR coregulators in CRPC.
- To elucidate the dual role of GNL3 in AR transcriptional programs.
- To investigate GNL3 as a potential therapeutic target in advanced prostate cancer.
Main Methods:
- Proteomic profiling of CRPC and primary prostate cancer cells.
- Assessment of GNL3 interaction with AR and its effect on chromatin occupancy.
- Analysis of GNL3's impact on cell proliferation and immune gene expression.
- Evaluation of GNL3 knockdown effects on CRPC cell sensitivity to AR antagonists and tumor progression.
Main Results:
- G Protein Nucleolar 3 (GNL3) was identified as a novel AR coregulator.
- GNL3 enhances AR-mediated transcription of proliferation genes (e.g., NEK2, CDC20).
- GNL3 represses immune-responsive genes (e.g., CXCL10, TAP1) via HDACs, promoting immune evasion.
- Increased GNL3 expression correlates with poor clinical outcomes in prostate cancer.
- GNL3 knockdown sensitizes CRPC cells to AR antagonists and reduces tumor growth/metastasis.
Conclusions:
- GNL3 acts as a dual-function AR coregulator, promoting proliferation and immune suppression in CRPC.
- GNL3 is a promising therapeutic target for advanced prostate cancer.
- Combinatorial inhibition of NEK2, HDACs, and AR signaling may represent a viable therapeutic strategy for CRPC.
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