GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE298nnn/GSE298827/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298827GEOGSEfalseA UBA6-UBE2Z-UBR2 Ubiquitination Cascade Sustains Tumor-Specific β-Catenin Activation through Intracellular E-cadherin Ubiquitination and Degradation [RNA-Seq]Aberrant Wnt/β-catenin signaling plays a pivotal role in tumorigenesis, particularly in colorectal cancer (CRC) development. Herein, through integrative analysis of genome-scale CRISPR datasets and functional validations, we identified ubiquitin-conjugating enzyme E2Z (UBE2Z), an E2 enzyme charged exclusively by the non-canonical ubiquitin-activating enzyme UBA6, as a general co-activator of oncogenic β-catenin. UBE2Z shows a strong functional correlation with β-catenin in pan-cancer analysis, and is critical for the growth of β-catenin-dependent cancer lineages. Notably, UBE2Z knockout significantly reduces nuclear β-catenin levels while minimally affecting its total/cytoplasmic expression. UBE2Z ablation diminishes β-catenin target gene expression and its chromatin binding, leading to a differentiation phenotype in CRC cells. Importantly, UBE2Z is dispensable for Wnt3a-induced physiological β-catenin accumulation and transcriptional activity. Cre-mediated conditional UBE2Z ablation does not disrupt intestinal integrity or structure, implying a dispensable role of UBE2Z in Wnt-mediated intestinal homeostasis. Moreover, we found a close correlation between UBE2Z and nuclear β-catenin in CRC specimens and that UBE2Z-deficient CRC xenografts exhibited strikingly reduced proliferation and a differentiation phenotype. Genome-wide CRISPR screening and secondary validation identified CDH1/E-cadherin as a key intermediary of UBE2Z-facilitated β-catenin activity. Mechanistic investigation revealed that the UBA6-UBE2Z cascade regulates β-catenin activity via modulating intracellular E-cadherin ubiquitination and degradation. Finally, we demonstrate that UBE2Z facilitates E-cadherin degradation via the UBR1~3 N-end rule E3 ligases. Taken together, our study revealed that the UBA6-UBE2Z cascade plays a crucial role in fueling constitutive β-catenin activity via E-cadherin ubiquitination and degradation.2026/06/01GSE298827GSM9024579GSM9024578GSM9024575GSM9024574GSM9024577GSM9024576GSM9024581GSM9024573GSM902458011154298827Homo sapiens