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Results for “WT1 Proteins”

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PubMed2020

GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression.

The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. SIGNIFICANCE: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.

A549 Cells↗

PubMed2025

Long noncoding RNA H19 promotes the acquisition of a mesenchymal-like invasive phenotype in mesothelial primary cells through an HDAC1-mediated WT1/Sp1 switch.

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in pro-inflammatory conditions, including peritoneal dialysis (PD), a renal replacement therapy. Characteristic of this process is the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT), a cell-specific form of EMT. Long noncoding (lnc) RNAs act as major players in physiologic regulatory circuitries of the cell. While LncRNA-H19 (lncH19), one of the first lncRNAs identified, has been broadly studied in tumorigenesis, its role in peritoneum fibrotic diseases has been scarcely addressed so far. Aim of this study was to investigate the role of H19 in the acquisition of a mesenchymal-like phenotype in primary fibrotic MCs from PD patients, and to elucidate epigenetic mechanisms controlling its expression. Genetic silencing/ectopic expression experiments revealed that H19 promoted the expression of MMT markers while downregulating the epithelial marker E-Cadherin, and favored MC directed migration and invasion on a collagen matrix. Silencing of three main H19 isoforms revealed a synergistic activity in the induction of a mesenchymal phenotype. Treatment with MS-275, an HDAC1-3 specific inhibitor previously known to promote MMT reversal, as well as HDAC1 genetic silencing, downregulated lncRNA H19 expression. Bioinformatic analysis revealed a binding sequence of Wilm's Tumor Protein 1 (WT1), the master gene of mesothelial differentiation, on the H19 promoter at an area with multiple acetylation peaks partially overlapping the binding site of Specificity protein 1 (Sp1), another transcription factor active in cellular plasticity regulation. Genetic silencing and Chromatin Immunoprecipitation (ChIP) experiments demonstrated that HDAC1 inhibition promotes a switch between WT1 and Sp1 in H19 promoter occupancy, favoring an inhibitory effect of WT1 on H19 expression and the reversal towards an epithelial-like phenotype. Overall, we discovered an HDAC1-WT1/Sp1-H19 axis potentially relevant to the design of new therapies aimed at counteracting peritoneal fibrosis.

RNA, Long Noncoding↗

PubMed2025

EWS::WT1 Isoform-Dependent Regulation of Neogenes in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma characterized by the pathognomonic EWS::WT1 fusion protein (FP), an oncogenic chimeric transcription factor (OCTF) resulting from the t(11;22)(p13;q12) translocation. Recent studies have identified "neogenes" (NGs), genes normally silent in normal tissues but transcriptionally activated by OCTFs, as potential tumor-specific markers in fusion-driven cancers. In this study, we investigated the expression and regulation of DSRCT-specific NGs (DSRCT_NGs) using multimodal data across different cohorts of patients, PDX, and cell line data. We evaluated bulk and single-nucleus RNA sequencing of patient specimens from MD Anderson Cancer Center, revealing the robust ability for DSRCT_NGs to distinguish FP-positive DSRCT from samples failing detection of the EWS::WT1 FP. To elucidate the regulatory role of the EWS::WT1 FP in driving NG expression, we performed knockdown experiments in four DSRCT cell lines. This consistently resulted in a reduction of DSRCT_NG expression. Isoform-specific expression of EWS::WT1 in LP9 and MeT-5A mesothelial cells revealed that the E-KTS isoform of EWS::WT1 predominantly drives DSRCT_NG expression. Mechanistically, ATAC-seq and ChIP-seq analyses demonstrated that EWS::WT1 directly binds to accessible chromatin regions near NG transcription start sites, enriched for WT1 motifs and active histone marks. Integration of Hi-ChIP data further revealed that EWS::WT1 facilitates long-range enhancer-promoter looping at DSRCT_NG loci, promoting the expression of nearby genes. Collectively, these findings establish DSRCT_NGs as direct transcriptional outputs of the EWS::WT1 FP and implicate their loci as regulatory regions of the DSRCT transcriptome. Their fusion-dependent expression, chromatin accessibility, and promoter-enhancer connectivity underscore their potential utility as highly specific biomarkers and therapeutic targets in DSRCT.

DSRCT↗

PubMed2026

CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles.

UNLABELLED: Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target lineage-specific surface antigens. However, CAR T cells show limited efficacy against myeloid neoplasms and solid tumors due to challenges in identifying suitable surface targets. In this study, we present a CAR targeting the intracellular WT1 oncoprotein, cross-presented by surface HLA class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1- and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This approach broadens CAR-targetable antigens beyond traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. SIGNIFICANCE: Leveraging the promiscuous binding of HLA-II-peptide complexes, we developed a CAR T-cell approach targeting an intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study establishes a framework for CAR therapies against intracellular antigens, extending potential CAR T-cell applications to new cancer types and patient populations.

Humans↗

PubMed2026

FOXC2 and WT1 regulate transcriptional reprogramming during the podocyte response to injury.

Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.

Animals↗

PubMed2026

Mechanism of Action of Hedyotis diffusa Extract in a Rat Model of Acute Lung Injury Based on Transcriptomic Analysis.

OBJECTIVE: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, collagen deposition, inflammatory cytokine levels, and key gene/protein expression following Hedyotis diffusa water extract (HDWE) intervention. Combined with ultra-high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), transcriptomic analysis, and molecular simulation, this study identified the bioactive components of HDWE, evaluated their potential interactions with ALI-related targets, and explored the multi-omics-based protective mechanisms of HDWE. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: Control group, ALI group, DXMS group, HDWE-L group (100 mg/kg), HDWE-M group (200 mg/kg), and HDWE-H group (300 mg/kg). Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate lung pathological changes and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum tumor necrosis factor-α TNF-α interleukin-1β IL-1β, erleukin-6 (IL-6), and interleukin-10 (IL-10) levels. Transcriptomic analysis identified differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), receiver operating characteristic (ROC), and immune infiltration analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) detected the mRNA expression levels of SPHK1, RELA, and NFKBIA. Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS characterized HDWE constituents. Molecular docking analysis was performed between 22 compounds and eight hub targets, followed by 100 ns molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) binding free energy calculations for five core targets. Compared with the control group, the ALI group showed increased levels of TNF-α (86%), IL-1β (107%), and IL-6 (66%), accompanied by a 43% reduction in IL-10 and a 300% increase in lung collagen deposition. All HDWE doses alleviated inflammatory responses, with medium-dose HDWE showing the most pronounced effects. Specifically, medium-dose HDWE increased IL-10 levels by 52% and reduced IL-6, TNF-α, and IL-1β levels by 18%, 22%, and 11%, respectively. Transcriptomic analysis identified 2512 DEGs between the control group and ALI groups, 832 exclusive DEGs between the ALI group and HDWE-M groups, and 876 overlapping DEGs enriched in TNF, IL-17, and NF-κB signaling pathways. The eight-hub-gene diagnostic model achieved an area under the curve (AUC) of 0.969. RELA, SPHK1, and four other hub genes showed positive correlations with Th1, Th17, and neutrophil infiltration. In the ALI group, SPHK1, RELA, and NFKBIA mRNA expression levels were 1.30-, 0.96-, and 0.71-fold of those in the control group, respectively. Compared with the ALI group, high-dose HDWE treatment and low-dose HDWE treatment reduced SPHK1 expression to 0.62- and 0.57-fold, respectively, and increased NFKBIA expression to 1.68- and 1.58-fold, respectively. High-dose HDWE treatment reduced RELA expression to 0.43-fold. The expression levels of inflammation-related proteins were increased in the ALI group and were reduced after HDWE treatment. Twenty-two HDWE components were identified, 16 of which met the docking criteria. Asperulosidic acid exhibited favorable predicted binding affinities with all eight targets, with calculated binding free energies of -14.74, -14.92, -17.58, -23.04, and -16.10 kcal/mol for MPO, IL-17, NF-κB p65, PTGS2/COX-2, and SPHK1, respectively. CONCLUSIONS: This study provides systematic in vivo pharmacodynamic and in silico component-target evidence regarding the protective effects of HDWE against LPS-induced ALI. HDWE treatment increased NFKBIA expression and reduced SPHK1, RELA, and multiple inflammatory protein levels, suggesting that HDWE may regulate the IL-17/NF-κB-associated inflammatory network, although direct causal relationships require further validation. Asperulosidic acid may represent a key bioactive component with broad target-binding potential. This study was limited by the use of an LPS-induced rat ALI model without gene knockout or target inhibitor validation; therefore, further functional experiments are required to confirm the proposed regulatory mechanisms.

Hedyotis diffusa↗

PubMed2025

A Subset of Serous Tubal Intraepithelial Carcinoma (STIC)-Like Lesions and Concurrent High-Grade Endometrial Carcinoma Are Genomically Related Entities.

In patients with high-grade endometrial carcinoma (HG-EC), concurrent isolated serous tubal intraepithelial carcinoma (STIC) or STIC-like lesions (STIC-LLs) in the fallopian tube(s) may be found. We sought to determine whether concurrently diagnosed HG-ECs and STIC-LLs are genetically related. Six HG-ECs, including serous carcinomas (n = 4) and carcinosarcomas with serous epithelial component (n = 2), with cooccurring STIC-LLs were identified and subjected to microdissection, DNA extraction, and panel sequencing targeting 468 cancer-related genes or, if DNA quantities were limited, to Sanger sequencing. WT1 and p53 protein expression was assessed by immunohistochemistry. We found that 3 HG-ECs and concurrent STIC-LLs shared pathogenic mutations, such as TP53 hotspot, NF2, FBXW7, and PIK3CA mutations. Immunohistochemical analysis revealed that the HG-EC of case 5 lacked WT1 expression and had aberrant p53 expression, although the matched STIC-LL displayed diffuse WT1 expression. Of the remaining 3 cases that did not show evidence of genetic relatedness based on the targeted sequencing panel, 1 STIC-LL harbored a clonal TP53 missense mutation, whereas the matched HG-EC had a distinct clonal TP53 hotspot mutation, a clonal FBXW7 hotspot mutation, and ERBB2 amplification. At the protein level, the p53 expression patterns of the HG-ECs and STIC-LLs were concordant in these 3 cases. Here, we demonstrate that cooccurring HG-ECs and STIC-LLs are genetically related in a subset of cases.

Humans↗

PubMed2026

Mismatch repair protein MLH1 controls testis development by regulating the Hippo-YAP signaling pathway.

DNA mismatch repair (MMR) maintains genomic stability, and defects in MMR genes such as MLH1 and MSH2 predispose to cancer. Unlike other MMR components, MLH1 has unexplained roles in development, as Mlh1-deficient male mice exhibit severe testicular hypoplasia and sterility. Here, we uncover that MLH1 regulates testis development through the Hippo-Yes-associated protein (YAP) pathway. MLH1 directly binds YAP via its C-terminal domain and the WW domains of YAP, competitively inhibiting LATS1-mediated YAP phosphorylation. This interaction stabilizes YAP by suppressing ubiquitination and promotes its nuclear translocation dependent on MLH1's nuclear localization signal. Additionally, MLH1 facilitates YAP-TEAD complex formation, enabling expression of testicular development genes, including Wt1, Sox9, and Ctgf. These functions are independent of the MMR activity of MLH1. Mlh1-deficient mice show elevated YAP phosphorylation, reduced target gene expression, and impaired proliferation in developing testes. Pharmacological inhibition of the Hippo pathway kinases MST1/2 partially rescues testis hypoplasia in Mlh1-/- mice. These findings establish MLH1 as a Hippo pathway regulator and resolve its long-standing role in male gonad development.

Male↗

PubMed2003

Organic anion and cation transporters occur in pairs of similar and similarly expressed genes.

Organic anion and cation transporters (OATs, OCTs, OCTNs, and ORCTLs), transmembrane proteins essential to renal xenobiotic excretion, are encoded by a group of related genes. As yet there have been no studies of the transcriptional regulation of this important gene family. While such studies have traditionally been labor-intensive, comparative genomics approaches are now available that have proven reliable guides to critical regulatory elements. We report here the genomic sequencing of murine OAT1 (the cDNA of which was originally cloned by us as NKT) and OAT3 (Roct), and derivation of phylogenetic footprints (evolutionarily conserved non-coding sequences) by comparison to the human genome. We find binding sites within these footprints for several transcription factors implicated in kidney development, including PAX1, PBX, WT1, and HNF1. Additionally, we note that OATs and OCTs occur in the human and mouse genomes as tightly linked pairs (OAT1 and OAT3, UST3 and OAT5, OAT4 and URAT1/RST, OCT1 and 2, OCTN1 and 2, ORCTL3 and 4) that are also close phylogenetic relations, with Flipt1 and 2, and OAT2 the only unpaired family members. Finally, we find that pair-members have similar tissue distributions, suggesting that the pairing might exist to facilitate the co-regulation of the genes within each pair.

5' Flanking Region↗

PubMed2026

Human and mouse adrenal glands are characterized by species-specific steroidogenic states and tissue turnover.

The adult adrenal cortex undergoes constant renewal, yet underlying human-specific mechanisms remain poorly understood. Here we generated single-cell and spatial transcriptomic atlases of adult human and mouse adrenal glands, leveraging single-cell-resolution spatial data and a rare clonal mosaic case for lineage inference. In humans, we identified age-associated zona glomerulosa (ZG) cell states with direct cortisol synthesis capacity and sex-specific differences in inferred cholesterol balance. Cross-species comparison revealed conserved aldosterone-producing ZG but notable divergence in zona fasciculata markers, absence of zona reticularis homologs in mice and differential SHH-WNT4 signaling in proliferating cells. We uncovered human WT1- capsule-to-ZG transition and vascular smooth muscle cell-to-steroidogenic transitions supported by mosaic lineage evidence. We revealed dispersed proliferating cortical SF1+EZH2+ cells throughout the human cortex in contrast with ZG restriction in mice. Taken together, our data expand the centripetal renewal model and establish a comparative framework for human adrenocortical biology.

Animals↗

PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗