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GNL3 orchestrates AR transcriptional programs to drive castration-resistant prostate cancer and immune evasion [ChIP-seq]

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305109 | GEO | 2026/05/13

REPOSITORIES: GEO

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Project description:ARv7, the most prevalent androgen receptor (AR) variant in castration resistant prostate cancer (CRPC), lacks the AR ligand binding domain (LBD) making it resistant to LBD-targeting pharmacological inhibitors, such as enzalutamide. Identifying new prostate cancer therapeutic targets by defining key coregulators (CoRs) and associated regulatory enzymes that govern AR and ARv7 transcriptional activity is critically needed. Here, we have developed a cell-free DNA pulldown assay employing androgen response elements (AREs) to isolate and characterize the AR/ARv7 CoR complexes formed on DNA. Mass spectrometry analyses of ARE pulldowns revealed previously undescribed AR and ARv7 interacting coregulators. ARv7 has enhanced recruitment of a subset of AR interacting CoRs, such as ANP32A and CAND1. SMRT, a known AR corepressor, is recruited with AR in the presence of androgens, but not with ARv7. Knockdown of ANP32A or CAND1 in prostate cancer cells reduced the expression of AR and ARv7 target gene expression, suggesting they function as coactivators. Bioinformatic analyses in human prostate cancer clinical datasets revealed that ANP32A and CAND1 expressions correlated with metastatic prostate cancer, poorer patient prognosis, and increased risk of recurrence. Additionally, DNA-dependent protein kinase (DNA-PK) was identified as an enzyme that directly phosphorylates AR and ARv7 and coactivates their transcriptional activities. DNA-PK action also stabilizes the interactions of ANP32A and CAND1 with AR and ARv7 complexes. Collectively, these findings suggest that DNA-PK coactivates the AR and ARv7 CoR complexes through its enzymatic function and by stabilizing the interaction of coactivators such as ANP32A and CAND1. Loss of SMRT recruitment combined with enhanced interaction of coactivators may contribute to unregulated ARv7 hyperactivity. Therefore, combination therapeutic approaches targeting AR/ARv7, DNA-PK, and ANP32A/CAND1 may lead to improved patient prognosis and novel prostate cancer treatment strategies.

Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL

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GNL3 orchestrates AR transcriptional programs to drive castration-resistant prostate cancer and immune evasion [ChIP-seq]

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