What question did this study set out to answer?

This research aims to uncover synthetic lethality in colorectal cancer by targeting the UBE2Z-UBR2-E-Cadherin axis in relation to beta-catenin.

April 5, 2026

Abstract 306: Integrative computational and functional genomic approach reveals UBE2Z-UBR2-Ecadherinaxis as a beta-catenin-specific vulnerability in colorectal cancer.

Key Points

This research aims to uncover synthetic lethality in colorectal cancer by targeting the UBE2Z-UBR2-E-Cadherin axis in relation to beta-catenin.
Utilized a machine-learning multi-omics approach to identify key components of oncogenic signaling.
Conducted genome-wide CRISPR rescue screens to explore UBE2Z interactions.
Performed transcriptomic and proteomic analyses to investigate E-Cadherin's role in beta-catenin signaling.
UBE2Z knockout disrupts nuclear beta-catenin accumulation and impairs Wnt target gene expression.
UBE2Z is found necessary for oncogenic beta-catenin activity but not for physiological Wnt signaling.
Identified E-Cadherin as a critical intermediary supporting oncogenic beta-catenin activity through degradation mechanisms.

Abstract

Abstract Synthetic lethality provides a powerful framework for cancer therapy by targeting gene interactions that are selectively essential in tumor cells, but are non-essential in normal tissues.. This approach is particularly attractive in malignancies driven by oncogenes considered “undruggable”. Using a machine-learning multi-omics approach we identify UBE2Z/USE1, a key ubiquitin-conjugating enzyme of non-canonical E1 UBA6-charged ubiquitination cascade, as a synthetic lethal partner of oncogenic β-catenin. UBE2Z knockout markedly impairs nuclear β-catenin accumulation, suppresses Wnt target gene expression, and induces differentiation in cell lines, tumouroids and in vivo models. Strikingly, UBE2Z is exclusively necessary for oncogenic β-catenin activity and completely dispensable for physiological Wnt/β-catenin signaling, highlighting its tumor-specific role. Genome-wide CRISPR rescue screens identified E-Cadherin as a critical intermediate of UBE2Z activity. Integrative transcriptomic and proteomics analyses suggest that UBE2Z supports oncogenic β-catenin transcriptional activity by promoting the degradation of intracellular E-cadherin via UBRfamily N-end rule E3 ligases. Manipulating UBE2Z’s ubiquitin-conjugating activity recapitulates the potent inhibitory effect of E-cadherin overexpression on oncogenic β-catenin activity, underscoring its translational significance. These findings reveal the UBA6-UBE2Z non-canonical ubiquitination cascade as a druggable vulnerability in β-catenin-addicted cancers and underscore synthetic lethality as a rational strategy for targeting β-catenin-driven tumorigenesis. Citation Format: Chunhua Wan, Hugh Gao, Claire Sun, Ron Firestein. Integrative computational and functional genomic approach reveals UBE2Z-UBR2-Ecadherinaxis as a beta-catenin-specific vulnerability in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 306.

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Cite This Study

Wan et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fdbfa79560c99a0a3fab https://doi.org/https://doi.org/10.1158/1538-7445.am2026-306

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