bims-meproc 2025-09-21 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–09–21
seventeen papers selected by
Grigor Varuzhanyan, UCLA

MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.
Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.
The important role of stress granules in prostate cancer development, progression, and drug resistance.
Novel Afro-Caribbean Prostate Cancer Model Reveals ancestry-specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.
Arrhythmic expression signatures of circadian clock-associated transcription factors and chronic circadian disruption contribute to advanced prostate cancer growth.
Three new phenanthrene derivatives from Pinalia densa and their cytotoxic activity against human prostate cancer cells.
Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer.
PRC2/FOXO1-Mediated Repression Determines Interchangeability of ETS Oncogenes in Prostate Cancer and Ewing Sarcoma.
Case Report: Genomic insights into prostate adenocarcinoma transdifferentiation to carcinosarcoma due to lineage plasticity.
Integrative single-cell and machine learning analysis predicts lactylation-driven therapy resistance in prostate cancer: a molecular docking and experiments-validated framework for treatment optimization.
SETD2 and EZH2: Two epigenetic drivers of prostate cancer.
A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.
A bioinformatics screen identifies TCF19 as an aggressiveness-sustaining gene in prostate cancer.
Development of a prognostic risk model for predicting biochemical recurrence-free survival in patients with prostate cancer based on lysine acetylation.
Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer.
[RNA-binding protein ELAVL1 regulates SOX4 stability and promotes hormone-sensitive prostate cancer proliferation through m6A-dependent regulation].
Marine-Derived Enteromorpha prolifera Polysaccharides Suppress Castration-Resistant Prostate Cancer via Akt1 Inhibition.

Prostate. 2025 Sep 19.

MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.

Changying Li, Chenchen He, Jiancheng Pan, Yuhong Feng, Dawei Tian, Jinhuan Meng, Zhi Qi, Changlin Li, Kuo Yang.

   OBJECTIVE: Androgen deprivation therapy (ADT) was the frontline treatment for patients with prostate cancer ineligible for radical prostatectomy. However, the development of resistance to ADT significantly limits its clinical efficacy.
METHODS: Using a genome-wide CRISPR/Cas9 knockout (GeCKO) library screen combined with single-cell RNA sequencing (scRNA-seq) analysis, we identified key genes involved in ADT resistance.
RESULTS: Macrophage migration inhibitory factor (MIF) was identified as a critical mediator of ADT resistance. Inhibition of MIF significantly overcomes ADT resistance. Moreover, we found that the androgen receptor (AR), but not its splice variant AR-V7, negatively regulates MIF expression. Consequently, inhibition of the AR signaling pathway via ADT results in the upregulation of MIF expression. Elevated expression of MIF promotes prostate cancer cell proliferation by upregulating AMPD2 expression.
CONCLUSIONS: Our findings demonstrate that ADT induces MIF upregulation, which in turn drives prostate cancer cell proliferation via upregulating AMPD2 expression, eventually contributing to the development of resistance to ADT.

Keywords:  MIF; androgen deprivation therapy; prostate cancer; purine metabolism; resistance

DOI:  https://doi.org/10.1002/pros.70053
Asian Pac J Cancer Prev. 2025 Sep 01. pii: 91865. [Epub ahead of print]26(9): 3157-3174

Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.

Ahmed S Alhallaq, Nadeen S Sultan.

  Metabolic reprogramming induced by the glutamine/glutamate (Gln/Glu) metabolic pathway is a key mechanism in ATP production, precursor biosynthesis, and redox homeostasis, promoting prostate cancer (PCa) growth and proliferation. This evolutionarily acquired hallmark of cancers enables malignant cells to adapt their bioenergetic and biosynthetic pathways in response to microenvironmental stresses. Therefore, Gln/Glu metabolism orchestrates epigenetic regulation, metastatic capacity, and oxidative homeostasis in PCa, supporting the survival of PCa tumors. Fluctuations in Glu metabolite levels and oxygen tension shape the PCa epigenome by facilitating Glu-derived α-ketoglutarate (α-KG) activation of TET and KDM enzymes, which drive histone and DNA demethylation. Furthermore, tumor progression toward metastatic castration-resistant PCa is characterized by heightened Gln/Glu dependency and increased Gln uptake. Within the tumor microenvironment (TME), a dynamic tug-of-war occurs between tumor and immune cells, competing for Gln metabolites. Gln/Glu converges on critical oncogenic signaling axes, including NF-κB/Nrf2, c-Myc/androgen receptor, MAPK/ERK, and PI3K/AKT/mTOR. Additionally, extracellular Glu release via SLC7A11 and PSMA triggers metabotropic glutamate receptor (mGluR) signaling, further potentiating oncogenic programs. Targeting this Gln/Glu metabolic network thus presents a promising therapeutic approach against PCa. In this review, we summarize the role of Gln/Glu in PCa progression based on the compartmentalization of the Gln/Glu metabolic pathway to elucidate why PCa cells manifest dependence on Gln/Glu. Eventually, we highlight potential therapeutic targets that can be exploited for PCa treatment.

Keywords:  Glutamine; Metabolic Reprogramming; Prostate Cancer; Tumor Microenvironment; glutamate

DOI:  https://doi.org/10.31557/APJCP.2025.26.9.3157
Gene. 2025 Sep 17. pii: S0378-1119(25)00565-7. [Epub ahead of print] 149776

The important role of stress granules in prostate cancer development, progression, and drug resistance.

Zhendong Xu, Hongjie You, Jun Gu, Junhui Jiang, Zejun Yan, Xiaofeng Jin.

  Prostate cancer (PCa) is the second most prevalent malignancy (7.3 %) and fifth leading cause of cancer death (4.1 %) in men globally. While lung cancer remains the predominant cancer in both incidence and mortality among all cancers, PCa exhibits geographically heterogeneous rising trends. Stress granules (SGs) are membraneless organelles formed through liquid-liquid phase separation (LLPS), playing a pivotal role in cellular stress responses, and are closely associated with various cancers, including PCa. Studies have shown that the expression of key SG-nucleating proteins, such as Ras-GTPase-activating protein-binding protein 1 (G3BP1), is upregulated in PCa, promoting the assembly of SGs. SGs can facilitate the initiation and progression of PCa by regulating mRNA stability, gene expression, and cellular signaling pathways, while also protecting cancer cells from damage under various stress conditions. Furthermore, SGs can modulate androgen receptor (AR) signaling, influencing PCa cell survival and sensitivity to androgen deprivation therapy (ADT). Additionally, SGs can promote PCa resistance to chemotherapy, including docetaxel (DTX), through interactions with various molecules involved in apoptosis, autophagy, and metabolism. This review summarizes the roles of SGs in the development, progression, and drug resistance of PCa, building on current advances in targeting SGs, highlights their promising potential as novel therapeutic targets for inhibiting malignant cancer progression, overcoming therapeutic resistance, and advancing PCa treatment strategies.

Keywords:  Androgen deprivation therapy; Chemotherapy resistance; G3BP1; Liquid-liquid phase separation; Oncogenesis; Prostate cancer; Stress granules

DOI:  https://doi.org/10.1016/j.gene.2025.149776
Cancer Res Commun. 2025 Sep 15.

Novel Afro-Caribbean Prostate Cancer Model Reveals ancestry-specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.

Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Tanisha Maitre, Magdalene Nwokocha, Rory Thompson, Belinda Morison, Rajini Haraksingh, Valerie Odero-Marah, Camille Ragin.

In the era of targeted therapeutics, the inadequate representation of Black populations in prostate cancer (PCa) models limits effective drug screening. Here, we introduce ACRJ-PC28, a novel Afro-Caribbean PCa cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses to those of established PCa cell lines from Black (MDA-PCA-2b) and White (DU-145, PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: Abiraterone showed remarkable selectivity for ACRJ-PC28 (IC₅₀ = 1.10 μM), being 4.6-13.1 fold more potent than in other cell lines, while Enzalutamide demonstrated pronounced racial differences, being 3-5 times less effective in cell lines from Black donors (IC₅₀ = 206 μM for ACRJ-PC28; 104 μM for MDA-PCA-2b) versus cell lines from White donors (IC₅₀ = 37 μM for PC-3; 48 μM for DU-145). RNA-seq analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in PCa cells from Black donors correlating with differential drug responses. Despite underexpressing AR, the ACRJ-PC28 line exhibited exceptional sensitivity to Abiraterone, consistent with clinical observations that Black patients with PCa respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within one year despite androgen deprivation therapy. Our findings suggest that incorporating diverse PCa models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate PCa mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0254
Int J Cancer. 2025 Sep 15.

Arrhythmic expression signatures of circadian clock-associated transcription factors and chronic circadian disruption contribute to advanced prostate cancer growth.

Ria Chopra, Haolong Li, Wenjuan Xie, Daniel Hau Tak Lam, Franky Leung Chan.

  Disruption of circadian rhythms due to night-shift work is classified as a probable carcinogen for cancers of the breast, prostate, and colorectum by the International Agency for Research on Cancer. Global epidemiological studies link chronic circadian clock disruption to increased risk of prostate cancer via hormone and metabolic dysregulation. This study investigated and compared the circadian expression patterns of core-circadian controlled genes (CCCGs) and nuclear receptors (NRs) under a normal 12-h light/dark cycle in normal mouse prostate and advanced androgen-insensitive prostate tumors derived from a transgenic mouse model of prostate adenocarcinoma (TGMAP). Our results showed that a total of eight CCCGs and 22 NRs exhibited rhythmic oscillations in the normal mouse prostate. In contrast, the rhythmic expressions of CCCGs and NRs were significantly disrupted in TGMAP prostate tumors, with a concurrent loss of androgen receptor expression. Circadian administration of cisplatin at a specific morning time point (chrono-chemotherapy), as applied in TGMAP tumor-bearing mice, demonstrated optimal antitumor efficacy, which correlated with the circadian rhythmic expression of DNA damage repair genes. Finally, we showed that chronic jet-lag conditions could promote the oncogenic growth of hormone-sensitive VCaP-derived xenograft tumors, with a correlation to elevated serum androgen levels and increased expression of enzyme genes involved in intratumoral androgen biosynthesis. Together, this study demonstrated that advanced prostate tumors exhibited dysregulated circadian transcriptional networks, as shown by their disrupted expression of CCCGs and NRs. The potential therapeutic application of chrono-chemotherapy in advanced prostate cancer management and the disruption of circadian rhythms under chronic jet-lag conditions could enhance prostate cancer growth.

Keywords:  chronic circadian disruption; chrono‐chemotherapy; circadian clock‐associated genes; nuclear receptors; prostate cancer

DOI:  https://doi.org/10.1002/ijc.70149
Nat Prod Res. 2025 Sep 13. 1-8

Three new phenanthrene derivatives from Pinalia densa and their cytotoxic activity against human prostate cancer cells.

Suthathip Ploithoom, Narumol Bhummaphan, May Thazin Thant, Chattarika Pengdee, Virunh Kongkatitham, Yanyong Punpreuk, Boonchoo Sritularak.

  Phytochemical analysis on the entire plant of Pinalia densa disclosed the existence of three new phenanthrene derivatives, named pinadensins A-C (1-3), in addition to ten known compounds (4-13). Structural elucidation of all new compounds was accomplished by several interpreting spectroscopic data such as CD, MS and NMR. Pinadensin A (1) and 9,9'-O-di-(E)-feruloyl-(-)-secoisolariciresinol (12) induced cytotoxic effects in human prostate cancer cell lines (PC-3 and DU145) as well as human normal keratinocyte HaCaT cells in relation to the dose; with an IC50 value of 30.97 ± 9.0 μM, liparisphenanthrene B (11) demonstrated significant cytotoxic action on PC-3, while having a less cytotoxic impact on HaCaT cells.

Keywords:  DU145; PC-3; Pinalia densa; cytotoxicity; orchidaceae; phenanthrene derivatives

DOI:  https://doi.org/10.1080/14786419.2025.2559754
Oncogene. 2025 Sep 19.

Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer.

Yuqiu Ge, Peiyu Han, Yangyang Sun, Yuyu Chen, Qianqian Shi, Li Cui, Qinbo Yuan, Gaoxiang Ma.

Aging significantly influences the pathogenesis of prostate cancer (PCa). Emerging evidence suggests that aging-related methylation changes play a critical role in PCa. However, the impact of aging-related DNA methylation in PCa remains largely unexplored. To identify hypermethylated sites associated with aging in PCa, we performed an epigenome-wide analysis using Illumina Human Methylation BeadChip arrays. The candidate methylation markers were further refined through least absolute shrinkage and selection operator (LASSO) regression and Random Forest model. Besides, we investigate the functional role of ZNF573 in PCa. Our analysis identified four aging-related CpG sites in the promoter region of ZNF573 that exhibited significant hypermethylation in PCa. These four DNA methylation markers effectively distinguished PCa from benign prostatic hyperplasia (BPH) with high AUC (0.847), which was superior to PSA. Furthermore, the expression of ZNF573 was notably down-regulated in PCa, and its overexpression significantly inhibited PCa cells proliferation and invasion both in vivo and in vitro. ZNF573 acting as a transcription factor promoted the expression of the E3 ubiquitin ligase RNF19B, which regulated the ubiquitination of PIK3CA. These findings suggest that aging-related ZNF573 methylation could serve as a potential diagnostic biomarker for PCa, influencing the development and progression of PCa through the regulation of PIK3CA ubiquitination via RNF19B.

DOI: https://doi.org/10.1038/s41388-025-03579-7
Mol Cancer Res. 2025 Sep 19.

PRC2/FOXO1-Mediated Repression Determines Interchangeability of ETS Oncogenes in Prostate Cancer and Ewing Sarcoma.

Nicholas F Downing, Kaitlyn M Mills, Peter C Hollenhorst.

Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60-70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5 or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. Here, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with PRC2. This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges the ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provides a mechanism for ERG synergy with PTEN deletion in prostate cancer. Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0389
Front Oncol. 2025 ;15 1576048

Case Report: Genomic insights into prostate adenocarcinoma transdifferentiation to carcinosarcoma due to lineage plasticity.

Tomohiro Fukui, Arinobu Fukunaga, Yuki Teramoto, Maki Fujiwara, Kensuke Hikami, Takuro Sunada, Kei Mizuno, Yuki Kita, Takayuki Sumiyoshi, Takayuki Goto, Ryoichi Saito, Takashi Kobayashi, Shusuke Akamatsu.

  In prostate cancer, it is recognized that adenocarcinoma can transdifferentiate into neuroendocrine prostate cancer (NEPC) owing to lineage plasticity; however, transdifferentiation into other histological types remains uncertain. We present a case of a patient who underwent surgery for adenocarcinoma, which later recurred as prostate carcinosarcoma. Genomic analysis revealed a TMPRSS2-ERG fusion, confirming a common clonal origin and transdifferentiation from adenocarcinoma to carcinosarcoma. Additionally, we identified a frameshift mutation in TP53 and the loss of PTEN and RB1. Transcriptome analysis revealed enriched epithelial-mesenchymal transition and immune-related pathways, a pattern distinct from both adenocarcinoma and NEPC. To our knowledge, this is the first report that comprehensively evaluated the clonal origin of the rare prostate carcinosarcoma and characterized it using genomic and transcriptomic sequencing. It enhances our understanding of prostate cancer lineage plasticity and highlights the importance of developing novel therapies specifically targeted at prostate carcinosarcoma.

Keywords:  carcinosarcoma; case report; genomic analysis; lineage plasticity; prostate cancer; transdifferentiation

DOI:  https://doi.org/10.3389/fonc.2025.1576048
Front Immunol. 2025 ;16 1647384

Integrative single-cell and machine learning analysis predicts lactylation-driven therapy resistance in prostate cancer: a molecular docking and experiments-validated framework for treatment optimization.

Zhiyu Liu, Yuqi Li, Juan Wang, Yang Zeng, Qilong Wu, Xinyao Zhu, Tao Zhou, Qingfu Deng.

   Background: Prostate cancer (PCa) is a common malignancy in males. Predicting its prognosis and addressing drug resistance remain challenging. This study develops a novel prognostic model focusing on lactylation and resistance, which plays a crucial role in tumor biology.
Methods: Single-cell analysis was employed to identify subpopulations expressing lactylation-related genes. Transcriptomic sequencing was used to identify drug resistance-associated genes. Univariate Cox proportional hazards models and machine learning techniques were used to identify prognostic genes, assisting in the development of a risk assessment framework. Additionally, we investigated how features related to lactylation and drug resistance correlate with clinical characteristics, the tumor microenvironment, and treatment responses, revealing potential interconnections.
Results: In this study, a model composed of 29 biomarkers was developed by integrating single-cell data and machine learning algorithms. The model predictive efficacy was validated through Kaplan-Meier (KM) analysis, univariate Cox (HR=3.59, 95%CI: 2.78-4.63) and multivariate Cox (HR=2.81, 95%CI: 1.96-4.03) regression. Comprehensive analysis revealed significant differences in tumor immune dysfunction and exclusion (TIDE) scores, immunophenoscore (IPS) scores, and chemotherapy drug sensitivity between high-risk and low-risk groups, suggesting that specific biomarkers may be closely associated with prognosis. Furthermore, molecular docking analysis and experiments were conducted to explore the relationship between drug resistance and risk gene-encoded proteins.
Conclusions: The prognostic model effectively predicts the progression-free interval (PFI) and drug response, with accurate risk stratification for PCa patients. Our findings highlight the potential of risk genes in the development of personalized treatment strategies and enhancing PCa prognostic assessment.

Keywords:  biomarkers; drug resistance; lactylation; machine learning; prostate adenocarcinoma; single-cell sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1647384
J Cancer. 2025 ;16(12): 3673-3683

SETD2 and EZH2: Two epigenetic drivers of prostate cancer.

Jiamin Wang, Longquan Xiang, Haiyan Zhang, Xiangyu Zhang.

  Prostate cancer is a prevalent malignancy among men, characterized by complex mechanisms underlying metastasis and treatment resistance. Epigenetic modifications play a crucial role in regulating prostate cancer progression, particularly involving histone methyltransferases such as SET-domain containing 2 (SETD2) and Enhancer of Zeste homolog 2 (EZH2). SETD2 contributes to chromatin stability by catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3), and its downregulation is strongly correlated with increased invasiveness and epithelial-mesenchymal transition in prostate cancer. Conversely, EZH2, the catalytic subunit of Polycomb Repressive Complex 2, mediates gene silencing through H3K27me3 modification and is frequently overexpressed in advanced disease, promoting tumor metastasis and resistance to therapy. Notably, SETD2 regulates EZH2 stability through direct protein interactions, highlighting a coordinated epigenetic regulatory axis. Multi-omics studies have revealed that SETD2 loss induces aberrant DNA methylation and activates oncogenic signaling pathways, whereas EZH2 overexpression cooperates with PI3K-AKT pathway dysregulation to drive castration-resistant prostate cancer. Although inhibitors targeting SETD2 (e.g., EZM0414) and EZH2 (e.g., tazemetostat) demonstrate antitumor activity in preclinical models, their clinical efficacy remains constrained by drug resistance and tumor microenvironment heterogeneity. Emerging evidence suggests that combining epigenetic therapies with immunotherapy may enhance therapeutic outcomes. This review comprehensively systematically examines the molecular mechanisms underlying the SETD2/EZH2 axis in prostate cancer, providing a theoretical foundation for developing precision therapies based on SETD2- or EZH2-mediated epigenetic modifications.

Keywords:  EZH2; Epigenetic modifications.; Inhibitor; Prostate cancer; SETD2

DOI:  https://doi.org/10.7150/jca.115715
bioRxiv. 2025 Sep 03. pii: 2024.03.24.586276. [Epub ahead of print]

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.

Phillip Thienger, Irene Paassen, Xiaosai Yao, Philip D Rubin, Marika Lehner, Nicholas Lillis, Andrej Benjak, Sagar R Shah, Alden King-Yung Leung, Simone de Brot, Alina Naveed, Bence Daniel, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Andrea Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Yu Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K Y Ng, David A Quigley, Robert L Yauch, Mark A Rubin.

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). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

DOI: https://doi.org/10.1101/2024.03.24.586276
Mol Oncol. 2025 Sep 15.

A bioinformatics screen identifies TCF19 as an aggressiveness-sustaining gene in prostate cancer.

Amaia Ercilla, Jana R Crespo, Saioa Garcia-Longarte, Marta Fidalgo, Sara Del Palacio, Natalia Martin-Martin, Onintza Carlevaris, Ianire Astobiza, Sonia Fernández-Ruiz, Marc Guiu, Laura Bárcena, Isabel Mendizabal, Ana M Aransay, Mariona Graupera, Roger R Gomis, Arkaitz Carracedo.

  Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental in improving the survival rate of prostate cancer patients. By means of gene expression meta-analysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and negatively associated with the activity of the androgen receptor. By combining computational and empirical approaches, our data revealed that TCF19 is required for full metastatic capacity, and its depletion influences core cancer-related processes, such as tumor growth and vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells.

Keywords:  androgen signaling; metastatic prostate cancer; meta‐analysis; transcription factor 19; vascular permeability

DOI:  https://doi.org/10.1002/1878-0261.70118
Transl Androl Urol. 2025 Aug 30. 14(8): 2218-2234

Development of a prognostic risk model for predicting biochemical recurrence-free survival in patients with prostate cancer based on lysine acetylation.

Bin Cao, Huijun Chen, Luting Zhang, Fang Xiao, Qiaoting Liu, Lizhen Tang, Tao You, Qiufang Ouyang.

   Background: Lysine acetylation plays a critical role in prostate cancer (PCa) by modulating androgen receptor (AR) signaling. However, the exact mechanisms by which lysine acetylation impacts PCa prognosis remain unclear. The aim of this study was to investigate the mechanism by which lysine acetylation affects PCa prognosis by modulating the AR signaling pathway.
Methods: Data from The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD), GSE54460, and lysine acetylation-related genes (LARGs) were obtained from public databases and literature. Differentially expressed genes (DEGs) were identified in TCGA-PRAD, and key module genes associated with LARGs were selected using weighted gene co-expression network analysis (WGCNA). Candidate genes were identified by overlapping DEGs and key module genes. A biochemical recurrence-free (BCR-free) prognostic model was constructed and validated using BCR-free survival data from patients with PCa. Prognostic genes were further confirmed through machine learning. PCa samples were stratified into high- and low-risk subgroups based on the median risk score. A nomogram model was developed integrating clinicopathological features and risk scores to identify independent prognostic factors. Enrichment analysis, tumor microenvironment profiling, and drug sensitivity assessments were performed for the two risk subgroups.
Results: A total of 2,658 DEGs and 723 key module genes were analyzed, yielding 105 overlapping candidate genes. Five genes-UBXN10, ACOX2, PLCL1, PLS3, and SLIT3-were identified as BCR-free-related prognostic markers in TCGA-PRAD. The prognostic risk model revealed significantly lower BCR-free survival rates in the high-risk subgroup compared to the low-risk subgroup. A nomogram incorporating Gleason score, tumor stage (T stage), and risk score effectively predicted BCR-free survival in patients with PCa. Notably, natural killer (NK) cells, myeloid dendritic cells, endothelial cells, and fibroblasts were significantly correlated with PLS3 (|Cor| >0.3, P<0.05). Drugs such as cisplatin, MK-1775, and ulixertinib were identified as potential therapeutic agents for PCa.
Conclusions: Five BCR-free-related prognostic genes were identified as potential therapeutic targets. Additionally, a BCR-free-related prognostic risk model was developed, offering a robust tool for predicting BCR-free survival in patients with PCa.

Keywords:  Prostate cancer (PCa); biochemical recurrence-free survival (BCR-free survival); lysine acetylation; prognostic genes; prognostic risk model

DOI:  https://doi.org/10.21037/tau-2025-179
Cancer Sci. 2025 Sep 16.

Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer.

Masaru Tani, Koji Hatano, Yu Ishizuya, Toshiki Oka, Tomohiro Kanaki, Shunsuke Inoguchi, Akihiro Yoshimura, Yuki Horibe, Yutong Liu, Sassi Nesrine, Yohei Okuda, Akinaru Yamamoto, Toshihiro Uemura, Gaku Yamamichi, Takuji Hayashi, Yoshiyuki Yamamoto, Taigo Kato, Atsunari Kawashima, Takao Yamaguchi, Satoshi Obika, Kosuke Yusa, Norio Nonomura, Keisuke Nimura.

  Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase inhibitors (PARPIs), metastatic castration-resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as BRCA1/2 mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome-wide CRISPR-Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality-inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82-G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality-inducing factor in prostate cancer, showing that L82-G17 enhances the efficacy of olaparib, regardless of the BRCA mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.

Keywords:  CRISPR‐Cas9 knockout screening; LIG1 inhibitors; PARP inhibitor; prostate cancer; synthetic lethality

DOI:  https://doi.org/10.1111/cas.70194
Zhonghua Nan Ke Xue. 2025 Sep;31(9): 791-799

[RNA-binding protein ELAVL1 regulates SOX4 stability and promotes hormone-sensitive prostate cancer proliferation through m6A-dependent regulation].

Sha-Sha Min, Zhong-Lin Cai, Yan-Ting Shen, Zhong Wang.

OBJECTIVE: To investigate the expression of RNA binding protein ELAVL1 in prostate cancer (PCa), especially hormone-sensitive prostate cancer (HSPC), and its relationship with tumor proliferation. This study further aims to reveal the molecular mechanism by which ELAVL1 promotes HSPC proliferation by stabilizing SOX4 mRNA in an m6A-dependent manner.
METHODS: The expression of ELAVL1 in PCa tissues and its relationship with prognosis were analyzed in the Cancer Genome Atlas (TCGA) database, and the differences in HSPC and hormone-resistant prostate cancer (HRPC) were compared. And its relationship with prognosis were analyzed in the Cancer Genome Atlas (TCGA) database, and the differences in HSPC and hormone-resistant prostate cancer (HRPC) were compared. Western blot was used to detect ELAVL1 protein expression in PCa cell lines. After ELAVL1 knockdown by siRNA, cell proliferation was evaluated using CCK-8 assays, and changes in downstream target genes were detected by RT-qPCR. Tumor xenograft experiments in nude mice were performed to further assess the impact of ELAVL1 on tumor growth. The interaction between ELAVL1 and SOX4 mRNA was verified by RIP-seq. And the mRNA and protein levels of SOX4 after knockdown of ELAVL1 were detected by RT-qPCR and Western blot, respectively. CCK-8 was used to evaluate the effect of SOX4 knockdown on cell proliferation. MeRIP-qPCR was used to detect the m6A modification level of SOX4 and the effect of knocking down METTL3. RNA pull-down experiments verified the interaction between SOX4 RNA fragments and ELAVL1 protein. RNA stability experiments evaluated the effect of ELAVL1 knockdown on SOX4 mRNA stability.
RESULTS: The expression of ELAVL1 in PCa cells was higher than that in normal prostate epithelial cells. The prognosis of patients with high expression of ELAVL1 was significantly worse than that of patients with low expression. In the GSE32269 dataset, the expression level of ELAVL1 in HSPC was significantly higher than that in HRPC. After knocking down of ELAVL1 in LNCaP and VCaP cells, CCK-8 experiments showed that the cell proliferation ability was significantly affected after knocking down ELAVL1, and overexpressed ELAVL1 promoted the proliferation of HSPC cells. The results of in vivo studies showed that knockdown of ELAVL1 significantly inhibited the tumorigenic capacity of LNCaP cells and resulted in a marked reduction in xenograft tumor mass. The levels of SOX4 mRNA and protein in LNCaP and VCaP cells were significantly higher than those in normal prostate epithelial cells RWPE-1. RIP-qPCR confirmed the interaction between ELAVL1 protein and SOX4 mRNA. After knocking down of ELAVL1, the expression levels of SOX4 mRNA and protein were significantly decreased. After knocking down of SOX4, the proliferation ability of LNCaP and VCaP cells was significantly inhibited.
CONCLUSION: ELAVL1 is highly expressed in HSPC. High expression of ELAVL1 is associated with the proliferation of HSPC. SOX4 is a downstream molecule of ELAVL1 which promotes the proliferation of HSPC. ELAVL1 enhances the stability of SOX4 mRNA through an m6A-dependent mechanism.

Keywords: hormone-sensitive prostate cancer; ELAVL1; SOX4; prostate cancer; proliferation; m6A
J Gene Med. 2025 Sep;27(9): e70038

Marine-Derived Enteromorpha prolifera Polysaccharides Suppress Castration-Resistant Prostate Cancer via Akt1 Inhibition.

Pingfa Lin, Na Yao, Tingting Lin, Yanhui Zou, Weiling Lin, Yong Lin.

  Prostate cancer remains a leading cause of cancer-related mortality, with castration-resistant and metastatic forms posing significant therapeutic challenges. Marine-derived polysaccharides from Enteromorpha prolifera (EP) have emerged as promising anticancer agents due to their unique bioactive properties. In this study, we investigated the antitumor effects of EP on prostate cancer cells and elucidated its underlying molecular mechanisms. EP demonstrated selective cytotoxicity against aggressive DU145 prostate cancer cells. Mechanistically, EP induced G1/S cell cycle arrest, suppressed DNA synthesis, and inhibited epithelial-mesenchymal transition. Cellular thermal shift assays confirmed EP-Akt1 interaction, increasing the thermal stability of Akt1. These findings establish EP as a novel Akt1-targeting agent that simultaneously blocks proliferative and metastatic pathways in prostate cancer. In conclusion, our results highlight the therapeutic potential of EP as a multitargeted, marine-derived compound for prostate cancer treatment.

Keywords:  Akt1 inhibition; Enteromorpha prolifera polysaccharides; cell cycle arrest; epithelial‐mesenchymal transition; prostate cancer

DOI:  https://doi.org/10.1002/jgm.70038