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GNL3 orchestrates AR transcriptional programs to drive castration-resistant prostate cancer and immune evasion

ABSTRACT: Androgen receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate cancer (CRPC), yet the mechanism remains incompletely understood. Dysregulation of the AR co-regulatory network has emerged as a key driver of castration resistance. To identify AR-interacting proteins linked to CRPC progression, we performed proteomics-based rapid immunoprecipitation of endogenous proteins (RIME) analysis targeting AR in the CRPC cell line C4-2B.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Cell Culture

DISEASE(S): Prostate Cancer

SUBMITTER: Cuiting Zhang

LAB HEAD: Edwin Cheung

PROVIDER: PXD067138 | Pride | 2026-06-08

REPOSITORIES: Pride

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			Action	DRS
	AR_rep1_1.raw	Raw
	AR_rep1_2.raw	Raw
	AR_rep2_1.raw	Raw
	AR_rep2_2.raw	Raw
	AR_rep3_1.raw	Raw

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Publications

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

Zhang Cuiting C Cheong Tin Long TL Narwade Nitin N Dong Dandan D Deng Mokan M Miao Zhengqiang Z Ding Zhaoqiang Z Li Wenchao W Lei Kate Man Kei KMK Wei Gong-Hong GH Poon Terence Chuen Wai TCW Deng Chu-Xia CX Cheung Edwin E

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20260302 26

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 ...[more]

PMID: 41772945

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Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model

Project description:More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naÃ¯ve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. 4 samples in each group: androgen-dependent growth (AD), castration-induced regression nadir (ND), and castration-resistant regrowth (CR) stages

2010-06-08 | E-GEOD-21887 | biostudies-arrayexpress

Regulation of lipid homeostasis in treatment-resistant prostate cancer

Project description:Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we performed a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicated an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineated a subset of proteins consistently associated with ARI resistance.

2020-05-26 | PXD016836 | Pride

Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer

Project description:Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify a novel role of methionine adenosyltransferase 2a (MAT2A) as a driver of the androgen-indifferent state in ERG fusion-positive CRPC. We show that MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP sequencing coupled with mass spectrometry analysis of histone post-translational modifications show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites promoting the expression of pro-tumorigenic non-canonical AR target genes in CRPC models. Genetic and pharmacological inhibition of MAT2A in preclinical models reversed this transcriptional and epigenetic remodeling, promoting luminal differentiation and improving the response to AR and EZH2 inhibitors. This data reveals a previously unrecognized function of MAT2A in epigenetic reprogramming and a synthetic vulnerability to MAT2A inhibitors in ERG fusion-positive CRPC.

2024-06-06 | PXD042895 | Pride

Androgen Receptor Gene Expression in Prostate Cancer is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine Specific Demethylase 1

Project description:Androgen receptor (AR) is reactivated in castration resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contributing to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels the AR binds this site and represses AR gene expression through recruitment of lysine specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis and proliferation, while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not on suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile pre-castrated androgen dependent, 4d-post-castrated, and relapsed castration resistant VCaP xenograft tumors in 3 mice. Total RNA was isolated and amplified prior to hybridization against a common reference pool of prostate tumor cell lines.

2011-08-15 | E-GEOD-31410 | biostudies-arrayexpress

Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the WNT master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT.

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The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer.

Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity. Tumor Harvest. When tumor size reached approximately 1.5 cm in diameter (6-8 weeks after injection), and the serum PSA was greater than 50 ng/ml, animals were surgically castrated under methoxyfluorane anesthesia and monitored for PSA levels for several weeks. Animals were sacrificed by carbon dioxide asphyxiation when tumors were harvested at several points along the PSA curve (pre-castrate (11), regressing (6), nadir (10), recurring (6) and castration resistant (12). Tumor segments were placed in RNALater (Qiagen) and frozen immediately at -80M-BM-0C.weeks. Tumors were harvested at several points along the PSA curve. The epithelial:stromal ratio is consistent within this tumor model and varies 10% between tumors, as assessed by immunohistochemistry of cytokeratin 14 (epithelium) and vimentin (stroma).

2013-02-15 | E-GEOD-44319 | biostudies-arrayexpress

CHD1 Loss Hijacks SREBP2-mediated Cholesterol Biosynthesis to Fuel SPOP-deficient Prostate Cancer and Confers Resistance to Castration [scRNA-seq]

Project description:Androgen receptor (AR) is an important driver in the disease progression of castration-resistant prostate cancer (CRPC). Speckle-type BTB/POZ protein (SPOP) mutations stabilize AR and frequently co-occur with the loss of chromodomain helicase DNA-binding protein 1 (CHD1). We generated a new genetically engineered mouse model and prostate cancer cells model containing CHD1 deletion and SPOP mutation to study the underlying mechanism. We found CHD1 loss–induced cholesterol production supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors, leading to castration resistance.

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CHD1 Loss Hijacks SREBP2-mediated Cholesterol Biosynthesis to Fuel SPOP-deficient Prostate Cancer and Confers Resistance to Castration

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GATA2 facilitates steroid receptor coactivator (SRC) recruitment to the androgen receptor (AR) complex

Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.

2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress

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