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At least 19 recordsLinked to original sources
PubMed2026

Molecular determinants of AR-enhancer interaction and cistrome reprogramming in prostate cancer progression.

The androgen receptor (AR) is a key transcription factor in prostate cancer (PCa), whose enhanced and altered functions are known drivers of cancer progression. A key aspect of this is reprogramming of the AR cistrome, which consists of genome-wide enhancer-binding sites through which AR regulates gene expression. The magnitude and biological impact of the AR cistrome are impacted by the AR itself, including the responses to ligand, as well as the organization of the associated DNA response elements, and availability of pioneer factors, cofactors, and noncoding RNAs, all of which contribute to a functional transcription complex. In this review, we will examine, in the context of PCa progression, the factors that affect the binding of AR and its interacting partners at enhancers, with a focus on AR cistrome reprogramming. We also discuss the clinical utility of targeting the AR-enhancer nucleoprotein complex and the potential of using the AR cistrome as a prognostic tool.

Humans↗
PubMed2024

Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant.

BACKGROUND: Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood. METHODS: We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants. RESULTS: Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia. CONCLUSION: Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.

Adult↗
PubMed1978

Presence of arylsulfatase A (ARS A) in multiple sulfatase deficiency disorder fibroblasts.

Multiple deficiency disorder fibroblasts cultured in MEM-CO2 showed deficiencies of arylsulfatase A(ARS A) comparable to the deficiency in metachromatic leukodystrophy fibroblasts. However, the MSDD fibroblasts cultured in MEM-HEPES contained near normal levels of ARS A. Moreover, the enzyme from the latter fibroblasts was indistinguishable from ARS A of control fibroblasts on DEAE-cellulose chromatography, ratio of activity with several substrates, thermal inactivation, sensitivity to inhibitors, and precipitation by antiserum to human ARS A. These data support the conclusion that the ARS A genome is intact in MSDD fibroblasts and, by extension, in MSDD patients. Other sulfatases were present at levels ranging from mildly deficient to near normal but never as low as seen in the corresponding specific sulfatase deficient disorders.

Cell Line↗
PubMed1979

Lysosomal arylsulfatase deficiencies in humans: chromosome assignments for arylsulfatase A and B.

Genetics of human lysosomal arylsulfatases A and B (aryl-sulfate sulfohydrolase, EC 3.1.6.1), associated with childhood disease, has been studied with human-rodent somatic cell hybrids. Deficiency of arylsulfatase A (ARS(A)) in humans results in a progressive neurodegenerative disease, metachromatic leukodystrophy. Deficiency of arylsulfatase B (ARS(B)) is associated with skeletal and growth malformations, termed the Maroteaux-Lamy syndrome. Simultaneous deficiency of both enzymes is associated with the multiple sulfatase deficiency disease, suggesting a common relationship for ARS(A) and ARS(B). The genetic and structural relationships of human ARS(A) and ARS(B) have been determined by the use of human-Chinese hamster somatic cell hybrids. Independent enzyme segregation in cell hybrids demonstrated different chromosome assignments for the structural genes, ARS(A) and ARS(B), coding for the two lysosomal enzymes. ARS(A) activity showed concordant segregation with mitochondrial aconitase encoded by a gene assigned to chromosome 22. ARS(B) segregated with beta-hexosaminidase B encoded by a gene assigned to chromosome 5. These assignments were confirmed by chromosome analyses. The subunit structures of ARS(A) and ARS(B) were determined by their electrophoretic patterns in cell hybrids; a dimeric structure was demonstrated for ARS(A) and a monomeric structure for ARS(B). Although the multiple sulfatase deficiency disorder suggests a shared relationship between ARS(A) and ARS(B), independent segregation of these enzymes in cell hybrids did not support a common polypeptide subunit or structural gene assignment. The evidence demonstrates the assignment of ARS(A) to chromosome 22 and ARS(B) to chromosome 5. A third gene that affects ARS(A) and ARS(B) activity is suggested by the multiple sulfatase deficiency disorder.

Cell Line↗
PubMed1976

Isolation and characterization of aldose reductase from calf brain.

Aldose reductase activity (alditol: NADP+ 1-oxidoreductase, EC 1.1.1.21) from calf brain was separated into two protein fractions by DEAE chromatography. Further purifcation by molecular sieve chromotography and electrofocusing yielding two distinctive enzymes, which were designated AR I and AR II. AR I was purified 646-fold and found to have an isoelectric point of 6.18. AR I was most active as a monomer with a molecular weight of 29 000 and appeared to be in equilibrium with a less active dimer. AR II was purified 425-fold and found to have an isoelectric point of 4.88. The molecular weight of this enzyme was 30 000. Although both enzymes had specificity for aldoses as substrates, AR I had two to three times larger turnover numbers with aromatic aldehydes and hexonates than did AR II. AR I was activated by sulfhydryl compounds and exhibited biphasic double reciprocal plots. AR I was more sensitive to inhibition by high substrate and phenobarbital concentrations than was AR II. AR I and AR II did not have antigenic similarity as tested by Ouchterlony immunodiffusion and counter immunoelectrophoresis. An immunochemical cross-reaction was observed between AR II and lens aldose reductase.

Alcohol Oxidoreductases↗
PubMed2025

Donor-Derived Cell-Free DNA Stratifies Risk of Mortality and Graft Dysfunction in Severe Acute Cardiac Allograft Rejection.

BACKGROUND: Cardiac acute rejection (AR) is a risk factor for poor outcomes, however there are limited risk prediction models to stratify patients for death or sustained LV dysfunction. This study assesses the prognostic utility of percentage donor-derived cell-free DNA (%dd-cfDNA) at the diagnosis of AR for poor outcomes. METHODS: The prospective multicenter GRAfT study enrolled heart transplant recipients and collected serial plasma samples to quantitate %dd-cfDNA. AR was defined as acute cellular rejection (ACR), antibody-mediated rejection (AMR), as well as biopsy-negative AMR (donor-specific antibody positivity with LV dysfunction). AR was classified as mild-to-moderate (ACR grade 2 or AMR grade 1) or severe (ACR grade &#x2265;3, AMR grade &#x2265;2, or DSA+/LV dysfunction) and further stratified by a %dd-cfDNA threshold of 0.25%. Regression models assessed the association between AR and %dd-cfDNA levels at the AR diagnosis with the primary composite outcome of sustained LVEF decline <50% and/or death. RESULTS: The study included 275 patients and 3,190 %dd-cfDNA assessments. Over the median of 4.6 (IQR 1.8 - 5.0) years follow-up, 51 patients experienced the composite outcome of death or prolonged EF reduction, and 75 patients developed AR, including 16.2% patients with ACR, 9.4% with pathologic AMR, and 6.6% with DSA+/LV dysfunction. Thirty-two (42.7%) patients had severe AR and 43 (57.3%) had mild-to-moderate AR. Severe-but not mild-to-moderate-AR was associated with an increased risk of the primary composite endpoint (HR = 5.17, 95% CI 2.38 - 11.3, p < 0.001). Among those with severe AR, a %dd-cfDNA level greater than 0.25% at diagnosis was associated with a higher risk of the primary outcome (HR, 6.06, 95% CI, 1.78-20.6; p = 0.004). Percent dd-cfDNA remained elevated in severe AR patients with adverse outcomes. CONCLUSION: Severe AR with high %dd-cfDNA levels is associated with an increased risk of poor outcomes, offering novel prognostic utility.

Acute Rejection↗
PubMed2026

A Spatiotemporal Atlas of the Androgen Receptor Proximal Interactome.

Androgen receptor-interacting proteins (AR-IPs) number close to 1,000, yet their organization across subcellular space and time remains uncharted. Proximity labeling identifies direct partners and neighboring proteins, thereby expanding AR-IPs to AR-proximal interacting proteins (AR-PIPs). Using proximity labeling quantitative mass spectrometry (PL-qMS), we construct a spatiotemporal atlas of the cytosolic, microsomal, and nuclear compartments in LNCaP prostate tumor cells. PL-qMS recovered 82.2% of the known AR-interactome in extranuclear compartments and 84.2% in the nucleus, identifying 4,751 AR-PIPs that remodel across an androgen time course. The retromer formed an androgen-sensitive AR-proximal interaction network (AR-PIN) verified by proximity ligation assays (PLAs). Moreover, partial VPS26A disruption attenuated androgen-regulated transcription and mislocalized the AR coactivator TMF1, defining a retromer-AR-TMF1 axis. In the nucleus, AR-PINs recover 100% of the Launonen 2021 ChIP-SICAP chromatome and reveal a PLA-verified translation-to-transcription handoff involving eIF4G and 4E-BP1. This spatiotemporal atlas provides a proximal framework for probing AR function in cells.

Journal Article↗
PubMed2026

The Association of Allergic Rhinitis with Chronic Adenotonsillar Diseases and Chronic Rhinosinusitis: A Mendelian Randomization Study.

INTRODUCTION: Allergic rhinitis (AR) has long been considered to be associated with chronic adenotonsillar disease (CATD). However, their causal relationship remains unclear. This study aims to investigate the causal relationship between AR and CATD and to examine the mediating role of chronic rhinosinusitis (CRS) in this association. METHODS: This study employed a two-sample Mendelian randomization (MR) design using genetic instrumental variable analysis. Data for allergic rhinitis (AR) were obtained from the MRC IEU OpenGWAS data infrastructure, data for chronic adenotonsillar disease (CATD) from the FinnGen biobank, and data for chronic rhinosinusitis (CRS) from the GWAS Catalog. Several MR methods were applied. In addition, a two-step MR approach was used to investigate the mediating role of CRS in the relationship between AR and CATD. RESULTS: MR analysis identified a positive correlation between AR and CATD. IVW and weighted median analyses showed significant causal effects (beta = 0.55, 95% CI: 0.26 to 0.84); p <0.001). No causal association was found between CATD and AR. AR and CRS showed a positive correlation (beta = 1.38, 95% CI: 0.78 to 1.98; p = 6.5 &#xd7; 10-6). CRS had a beta value of 0.15 (95% CI: 0.06 to 0.24; p = 0.001) for CATD. CRS mediates 37.6% of the AR to CATD pathway (mediation effect = 0.20, 95% CI: 0.04 to 0.37; p = 0.013). DISCUSSION: These findings indicate that AR may contribute to CATD risk through CRS, highlighting the need for further research to explore underlying biological mechanisms and validate these findings. CONCLUSIONS: This study suggests a positive causal relationship between AR and CATD, with CRS acting as a mediator.

Mendelian Randomization Analysis↗
PubMed2025

The RNA helicase DDX17 enhances androgen receptor stability by interacting with the E3 ubiquitin ligase SPOP in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is a common malignancy in men, closely associated with androgen receptor (AR) signaling, and often diagnosed with elevated prostate-specific antigen (PSA). While androgen deprivation therapy (ADT) is effective, resistance develops due to reactivation of AR signaling, driving disease progression. We aimed to explore the role of DDX17 in the progression of PCa through its interaction with SPOP. We hypothesized that DDX17 can stabilize the AR by inhibiting SPOP-mediated ubiquitination, thereby maintaining AR signaling which supports tumor growth and survival. METHODS: We collected gene expression data and clinical information from PCa patients from The Cancer Genome Atlas and Gene Expression Omnibus databases. Messenger RNA (mRNA) and protein levels were quantified using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell viability and invasion capabilities were assessed using cell counting kit-8 (CCK-8) and transwell invasion assays. The interactions between DDX17 and SPOP were examined through coimmunoprecipitation assays. RESULTS: DDX17 exhibited high expression in both PCa tissues and cells. Silencing DDX17 led to reduced proliferation and invasion of PCa cells. Mechanistic investigations revealed that DDX17 directly interacted with SPOP, sustaining AR stability by preventing AR ubiquitination. These findings suggest a role of DDX17 in promoting the progression of PCa by binding and blocking SPOP ubiquitination of AR. CONCLUSIONS: This study elucidated a novel mechanism through which the RNA helicase DDX17 can promote PCa progression through its interaction with SPOP, thereby enhancing AR stability by inhibiting AR ubiquitination.

DDX17↗
PubMed2026

Targeting the Fatty Acid Binding Protein 5-Specificity Protein 1 Axis Restores Enzalutamide Sensitivity by Suppressing Androgen Receptor/Androgen Receptor Splice Variant 7 Signaling: Implications for Prostate Cancer Therapy.

BACKGROUND: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge driven by persistent androgen receptor (AR) signaling and constitutively active splice variants such as androgen receptor splice variant 7 (AR-V7), which confer resistance to therapies including enzalutamide. Although metabolic reprogramming contributes to disease progression, the integration of metabolic and transcriptional regulators sustaining therapeutic resistance remains incompletely understood. METHODS: We integrated clinical transcriptomic analysis of The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) cohort with mechanistic and functional validation in 22RV1 CRPC cells to investigate the role of the fatty acid binding protein 5-specificity protein 1 (FABP5-Sp1) regulatory axis. RESULTS: Transcriptomic analysis revealed that FABP5 is significantly upregulated in prostate tumors compared with normal tissue and increases with higher Gleason score. In contrast, AR and Sp1 exhibited heterogeneous expression patterns. Mechanistically, genetic ablation of FABP5 markedly reduced AR-V7 expression and restored sensitivity to enzalutamide, leading to suppression of AR signaling. Conversely, FABP5 overexpression increased Sp1 protein levels. Pharmacological inhibition of Sp1 using mithramycin A resulted in coordinated downregulation of FABP5, AR, and AR-V7, along with suppression of peroxisome proliferator-activated receptor gamma (PPAR&#x3b3;) signaling and downstream vascular endothelial growth factor A (VEGFA) expression. Functionally, Sp1 inhibition significantly reduced anchorage-independent growth and invasion. CONCLUSION: These findings define a FABP5-Sp1-AR/AR-V7 transcriptional-metabolic axis driving enzalutamide resistance in CRPC. Targeting FABP5 restores therapeutic sensitivity and represents a promising biomarker and therapeutic strategy in advanced prostate cancer.

AR-V7↗
PubMed2026

An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.

BACKGROUND: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource evaluation, the DCM gene curation expert panel reconvened in 2024-2025 to conduct a reassessment of genes in DCM. METHODS: The Clinical Genome Resource semiquantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories on the basis of strength of published evidence for a DCM phenotype. Previously curated genes were reassessed, and newly reported gene-disease-mode of inheritance (MOI) relationships, termed "curations," were evaluated. RESULTS: Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five reevaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2, for which curation was modified to separate autosomal dominant and AR MOI curations, clinically significant changes involved upgrades from low- to high-evidence categories (PLEKHM2, PRDM16, TBX20, TNNI3K), demonstrating the robustness of the Clinical Genome Resource gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including 6 newly evaluated genes and 1 new MOI for a previously evaluated gene, MYBPC3-AR; 4 were classified as No Known Disease Relationship, and remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs: JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong). CONCLUSIONS: With substantial new evidence, the genetic architecture of DCM has rapidly expanded. This updated assessment of genes reported in DCM yielded 35 high-evidence curations, an increase from 19 only 5 years ago. The results of this evidence-based evaluation process inform clinical interpretation of genetic information in the care of DCM patients and families.

dilated cardiomyopathy↗
PubMed2026

Phosphoproteomic analysis in a mouse model reveals ERK signaling as a key modulator of inflammatory response in nasal mucosa associated with childhood allergic rhinitis.

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.

Animals↗
PubMed2026

Ubiquitination-Androgen Receptor Coupling in Prostate Cancer Therapeutics.

Prostate cancer is one of the most frequently diagnosed malignancies in men and a leading cause of cancer-related mortality worldwide. The androgen receptor (AR) remains the principal driver of prostate cancer progression and castration-resistant prostate cancer (CRPC), with its stability, localization, and transcriptional activity being tightly regulated by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases and deubiquitinases (DUBs) critically govern AR turnover and signalling output, thereby influencing tumour growth, therapeutic resistance, and disease progression. Emerging evidence further highlights a complex interplay between ubiquitination, DNA damage response (DDR) pathways, and ADP-ribosylation (ADPr) signalling, collectively shaping genomic stability and treatment responsiveness in prostate cancer. This review is organized into four major themes: (i) ubiquitin-mediated regulation of AR signalling, (ii) ubiquitination and DNA damage response in AR-driven prostate cancer, (iii) crosstalk between ubiquitination, ADPr, and AR-associated signalling pathways, and (iv) therapeutic strategies targeting the UPS and AR axis. This study also discusses recent advances in targeted protein degradation, modulation of E3 ligases, inhibition of deubiquitinases, and PARP-based therapeutic approaches. These emerging insights into the interconnected regulation of ubiquitination, AR signalling, DDR pathways, and ADP-ribosylation may facilitate the development of next-generation therapeutic approaches for advanced prostate cancer.

ADP-ribosylation (ADPr)↗
PubMed1979

Aldose reductase in diabetic complications of the eye.

Aldose reductase (AR) appears to initiate the cataractous process in galactosemic and diabetic animals. Sugars in excess are converted to polyols by lens AR. In sugar cataracts, polyols accumulate to levels substantial enough to cause a hypertonicity leading to lens fiber swelling. All other changes appear secondary to polyol accumulation and lens swelling. The development of sugar cataracts can be duplicated in organ culture. In culture, the various changes that occur were minimized or did not occur when inhibitors of AR were included in the medium. Moreover, AR inhibitors were shown to effectively delay the onset of sugar cataract development in animals. A defect in the corneal epithelium of diabetics became apparent in vitrectomy. One manifestation of this problem was the delay in the reepithelialization of denuded corneas. In examining this problem experimentally, the epithelium was removed from the corneas of diabetic and normal rats. The regeneration of epithelium in corneas of diabetic rats required a longer period than in the normal. The possibility that AR, active in the epithelium, was involved in this phenomenon was investigated. The corneal epithelium was removed from both eyes of a diabetic rat. One eye was treated topically with the AR inhibitor CP-45,634 while the other served as control. The eye treated with CP-45,635 regenerated epithelium much more quickly than the untreated eye. Other AR inhibitors had similar beneficial effects.

Aldehyde Reductase↗
PubMed2026

All-inside repair is an effective treatment for medial meniscus posterior root tears: a systematic review and meta-analysis of biomechanical and clinical evidence.

BACKGROUND: Medial meniscus posterior root tears (MMPRTs) reproduce the biomechanics of subtotal meniscectomy. Repair is favored, but the role of all-inside repair (AR) remains unclear relative to transtibial pull-out (TP). This study aimed to review the biomechanical and clinical evidence on AR for MMPRTs. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO). MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Outcomes included patient-reported outcome measures (PROMs), magnetic resonance imaging (MRI), and biomechanical performance. When available, random-effects meta-analysis was performed. RESULTS: Thirteen studies were included. AR restored contact mechanics and showed load to failure comparable to TP, with lower stiffness. Meta-analysis showed lower conversion to total knee arthroplasty with AR versus non-repair (RR 0.18, 95% CI 0.05-0.58), and no significant PROM differences between AR and TP. CONCLUSIONS: AR showed favorable biomechanical properties and improved outcomes versus non-repair. Compared with TP, no significant clinical differences were observed. AR may represent a reasonable option in selected scenarios.

Humans↗
PubMed2025

LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer.

Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.

Male↗
PubMed2025

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

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.

Journal Article↗