PRDX1 drives colorectal cancer progression and immune microenvironment remodeling by facilitating PRMT5 nuclear translocation to activate Wnt/β-catenin signaling.
Aug 2026· International Journal of Biological Macromolecules· pp.
154238
· 0 citations· 40 references
Medicine
TL;DR
Findings identify a novel PRDX1-PRMT5 axis that activates Wnt/β-catenin signaling, highlighting a potential therapeutic strategy for CRC by targeting this pathway to suppress tumor progression and remodel the immune microenvironment.
Abstract
Hyperactivation of Wnt/β-catenin signaling drives colorectal cancer (CRC) progression and contributes to an immunosuppressive tumor microenvironment. Although peroxiredoxin-1 (PRDX1) is overexpressed in CRC and correlated with poor prognosis, its mechanistic role in Wnt/β-catenin-mediated immune evasion remains unclear. Through transcriptomic sequencing and co-immunoprecipitation, we identified PRDX1-interacting proteins and validated their functional roles via luciferase assays, mutagenesis, and pharmacological approaches in syngeneic models. Results demonstrated that PRDX1 knockout attenuated Wnt/β-catenin signaling in AOM/DSS-induced CRC mice. In cellular models, PRDX1 knockdown inhibited nuclear translocation of β-catenin by promoting its ubiquitination. Mechanistically, PRDX1 functions as a redox-sensitive chaperone that interacts with protein arginine methyltransferase 5 (PRMT5) in the cytoplasm and facilitates its nuclear translocation. This was associated with increased H3R2me2 and H3R8me2 levels, upregulation of DVL3 transcription, and subsequent Wnt/β-catenin activation. The interaction was abrogated by disrupting the Rossmann-fold or β-barrel domains of PRMT5, or by introducing the R368A catalytic mutation, suggesting that these domains are important for the PRDX1-PRMT5 association. Importantly, pharmacologically inhibiting PRMT5 suppressed PRDX1-driven tumor growth and alleviated immunosuppression in vivo by dampening Wnt/β-catenin signaling. These findings identify a novel PRDX1-PRMT5 axis that activates Wnt/β-catenin signaling, highlighting a potential therapeutic strategy for CRC by targeting this pathway to suppress tumor progression and remodel the immune microenvironment.
Aberrant Wnt/β-catenin signaling is frequently observed in gastric cancer (GC); however, the mechanisms sustaining this pathway in the absence of canonical genetic mutations remain incompletely understood. Here we show that the transcriptional cofactor LBH drives mutation-independent Wnt activation and malignant progression in GC via a tumour microenvironment-regulated post-translational stabilization mechanism. By integrating single-cell transcriptomics with multicentre clinical cohorts, we identify LBH as a principal regulator of epithelial–mesenchymal transition and peritoneal metastasis, and its elevated expression independently predicts poor patient survival. Mechanistically, fi broblast activation protein (FAP)-positive cancer-associated fi broblasts (CAFs) secrete TGF-β1, which selectively induces LBH expression in adjacent GC cells via the SMAD2/3 signaling cascade. Crucially, LBH physically interacts with β-catenin, providing steric hindrance that prevents destruction complex-mediated phosphorylation and subsequent ubiquitin-proteasomal degradation. This FAP⁺ CAF–TGF-β1–LBH–β-catenin paracrine axis continuously sustains global Wnt transcriptional output without requiring intrinsic genetic mutations. Our findings elucidate a critical tumour–stroma crosstalk mechanism and establish the targeted disruption of the LBH–β-catenin interaction interface as a clinically relevant therapeutic strategy for advanced gastric cancer.
Zhixiong Su, Guifeng Zhang, J. Zhong et al.· Cell Death & Disease· 0 citations
Summary The epithelial-mesenchymal transition is associated with the acquisition of cancer stem cell (CSC) traits that promote metastasis and therapy resistance. Here, we investigated the role of the E3 ubiquitin-ligase Hakai in regulating CSC-associated properties in colorectal cancer. Using tumoursphere models, loss-of-function approaches, proteomics, bioinformatics, and Wnt/β-catenin pathway studies, we found that Hakai depletion reduced tumoursphere formation, CSC marker expression, and Wnt target gene activation. Mechanistically, our findings support that Hakai regulates LRP4 stability, a negative regulator of Wnt signaling, consistent with ubiquitin-dependent mechanism. Consequently, Hakai enhances β-catenin/TCF transcriptional activity, nuclear accumulation of β-catenin, and attenuation of LRP4-mediated inhibition of Wnt signaling. Pharmacological inhibition of Hakai with Hakin-1, a selective inhibitor of its HYB domain responsible for E3 ubiquitin-ligase activity, reduced tumoursphere formation and promoted differentiation-associated features. Furthermore, these findings highlight Hakai inhibition as a potential CSC-directed therapeutic strategy in colorectal cancer.
Andrea Rodríguez-Alonso, Lía Jove, G. Alfonsín et al.· iScience· 0 citations
The Wnt/β-catenin pathway plays a critical role in colorectal cancer (CRC) development. The significance of Wnt/β-catenin in maintaining the stability of adult tissues and challenges in identifying suitable molecular targets have limited the application of targeting the Wnt/β-catenin pathway. As one of the Cullin RING Ligase 4 adapters, DNA damage-binding protein 1 (DDB1) - and CUL4 correlation factor 13 (DCAF13) appears strongly expressed in different tumors. Our findings confirm enhanced expression of DCAF13 in tissues of CRC origin and related cell. In colon cancer cells, DCAF13 regulated adenomatous polyposis coli membrane recruitment 2 (AMER2) through ubiquitination, DCAF13 deletion increased AMER2 expression, which inhibited Wnt/β-catenin activity, suppressing cell proliferation. This effect was further validated in mice with gut-specific DCAF13 knockout. The ubiquitin-proteasome system is a potential target for drug development and cancer treatment. Beta-propeller proteins, such as CRL4 adapter DCAFs, are easily targeted by drugs. DCAF-proteolysis-targeting chimeras (PROTACs) can overcome drug resistance and selectively target tumor drivers by leveraging the unique substrate specificity of the DCAF subunits. DCAF13 emerges as a promising target for CRC, acting via the DCAF13-AMER2-Wnt /β-catenin axis.
Yu-Xin Hua, Jie Gao, Qing Sun et al.· npj Precision Oncology· 0 citations
Wnt/β-catenin pathway activation is a hallmark of many cancers, with Wnt pathway mutations present in ∼40% of advanced HCC (aHCC). TBL1 functions as a central scaffold and chromatin-state regulator within the TCF/β-catenin transcriptional machinery and controls degradation of nuclear b-catenin and is required for assembly of the active transcriptional complex, promoting oncogenic Wnt signaling. Tegavivint is a first-in-class small-molecule inhibitor of TBL1, discovered in a chemical genomics screen as an inhibitor of β-catenin transcriptional activity. Binding of TBL1 by tegavivint disrupts theTBL1/β-catenin complex, resulting in selective degradation of nuclear β-catenin while preserving cytoplasmic and membrane-bound β-catenin functions associated with normal tissue homeostasis. This mechanism inhibits Wnt-driven oncogenicity while avoiding toxicities observed with upstream Wnt inhibitors, representing a novel downstream approach to targeting the Wnt pathway. Tegavivint has been evaluated in a phase 1/2 dose escalation study in advanced hepatocellular carcinoma (NCT05797805) in which the drug was well tolerated and demonstrated clinical responses in a heavily pre-treated population harboring Wnt-pathway mutations. Here, we present an integrated analysis of preclinical and clinical pharmacodynamic (PD) data characterizing tegavivint activity. Tumor mutational status was correlated with clinical status and patient outcomes. Clinical benefit was observed only in patients with mutations in the Wnt pathway genes, CTNNB1, AXIN1, APC, and CREBBP. Transcriptional signatures of tegavivint were analyzed by RNA-seq, demonstrating downregulation of Wnt/β-catenin target genes and induction of apoptotic pathways, consistent with transcriptional reprogramming via TBL1-mediated inhibition of β-catenin activity. Clinical pharmacodynamic effects were evaluated by IHC of paired tumor biopsies, which revealed reductions in active β-catenin following treatment, supporting on-target activity. Serum biomarker analysis showed modulation of Wnt-regulated proteins, including decreases in DKK1, FGF-2, MMP-1, PDGF-AA, and VEGF-A. These PD changes mirror those observed in desmoid tumor patients treated with tegavivint (NCT03459469), indicating mechanism-based biomarker changes across tumor types. The concordance of transcriptional, tissue-based, and circulating biomarkers provides compelling evidence of on-target inhibition of the TBL1/β-catenin transcriptional complex. Collectively, these findings establish TBL1 as a clinically actionable regulator of oncogenic transcription and demonstrate that tegavivint achieves pharmacodynamic modulation of the Wnt pathway through a differentiated downstream mechanism. This approach represents a novel strategy for targeting Wnt-driven cancers.
Aundrietta D. Duncan, Elena Ramirez, Julissa Simmons, Mahtab Youseffi, David D. Stenehjem, Stephen K. Horrigan. Pharmacodynamic evidence of Wnt/β-catenin inhibition by tegavivint, a TBL1-directed transcriptional modulator, in advanced hepatocellular carcinoma: a phase 1 study [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B069.
Aundrietta Duncan, Elena Ramirez, Julissa Simmons et al.· Clinical Cancer Research· 0 citations
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
