MICAL2 as a key effector of β-catenin signaling driving melanoma progression and therapeutic resistance.

Emerging role of ETV4 in colorectal cancer: from molecular mechanisms to clinical implications

ETV4 (ETS-transformation-specific variant 4) is a member of the ETS transcription factor family that has been extensively studied for its oncogenic functions in cancers. Here, we summarize the role and mechanisms of ETV4 in cancer biology, with a particular focus on colorectal cancer (CRC), as well as its biomarkers and therapeutic potential. As a transcription factor, ETV4 regulates the expression of target genes by recognizing the GGA(A/T) core conserved sequence. It is frequently overexpressed in pan-cancer, where its overexpression associated with poor prognosis. Upon activation by oncogenic signaling pathways (e.g., MAPK, PI3K/Akt, and WNT), ETV4 transcriptionally regulates downstream genes to promote tumor cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), chemoresistance, metabolic reprogramming, and immune evasion. It also form a vicious positive feedback loop that continuously activates oncogenic signaling. In CRC, ETV4 is overexpressed, correlating with advanced disease, lymph node metastasis, and poor prognosis. Upon activation by oncogenic signals, ETV4 directly activate target genes (such as matrix metalloproteinases) to mediate adenoma-to-adenocarcinoma progression, proliferation, EMT, ferroptosis, invasion, metastasis, metabolic reprogramming, and tumor microenvironment remodeling in CRC. ETV4 also forms transcriptional complexes with certain epigenetic factors, such as miRNAs and p300. Moreover, ETV4 is a promising biomarker for CRC diagnosis, prognosis, and adenoma-to-adenocarcinoma progression. Targeting ETV4 or its upstream pathways represents a potential therapeutic strategy for CRC. However, there are still many unresolved issues in current research. For example, the role of ETV4 in immune evasion and tumor microenvironment remodeling remains at the descriptive stage, and the specific mechanisms by which it regulates immune cell recruitment have not yet been elucidated. Future efforts include utilizing multi-omics approaches to elucidate the mechanisms by which ETV4 shapes the CRC microenvironment and exploring the application prospects in tumor immunotherapy.

PRDX1 drives colorectal cancer progression and immune microenvironment remodeling by facilitating PRMT5 nuclear translocation to activate Wnt/β-catenin signaling.

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.

Therapeutic targeting of β-catenin in cancer.

Mutations in β-catenin, together with recurrent genetic alterations affecting the WNT signaling pathway, define one of the most prevalent oncogenic axes, collectively occurring in approximately 10% of human cancers. Thus, β-catenin is a prime target for precision oncology. Over the three decades following the pathway's discovery, substantial progress has been made in elucidating how aberrant WNT/β-catenin signaling can drive cancer initiation, progression and maintenance. Attempts to therapeutically address this pathway have until recently been unsuccessful. Approaches to block the pathway upstream of relevant mutations were ineffective while progress in directly targeting β-catenin, either by blocking its interaction with key complex partners, most notably T cell factor (TCF) proteins, or by inducing β-catenin degradation has long remained an unreachable goal for conventional drug discovery approaches. In this review, we describe opportunities and challenges in the development of therapies that directly aim to target β-catenin. We highlight recent progress based on novel approaches, suggesting that cracking this previously considered "undruggable" central oncogenic driver is becoming a reality. Effective targeting of β-catenin has the potential to address extensive unmet patient needs in hard-to-treat cancer types such as colorectal cancer, hepatocellular carcinoma as well as other cancers driven by WNT/β-catenin pathway alterations.

The multifaceted role of SOCS3 in colorectal cancer: molecular mechanisms and clinical implications

CAF-derived TGF-β1 activates an LBH-mediated β-catenin stabilization program to drive gastric cancer progression

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.

Targeting JOSD2 degrades β-catenin to suppress colorectal cancer metastasis by disrupting RAS/ERK/β-catenin axis.