UFMylation-Dependent Stabilization of Emerin Suppresses Hepatocellular Carcinoma via β-Catenin

Hepatocellular carcinoma (HCC) ranks as a leading cause of cancer-related deaths. A recent article identified UFMylation as a suppressor of HCC metastasis. Xu et al. show that UFMylation is lost in HCC and this destabilizes the nuclear-membrane protein emerin, which promotes its degradation, thereby enabling the nuclear accumulation of β-catenin. Under physiological conditions, emerin prevents the nuclear localization of β-catenin. However, via nuclear β-catenin accumulation, loss of UFMylation leads to activation of transcriptional signatures associated with a pattern consistent with hybrid epithelial–mesenchymal transition (EMT), characterized by the expression of both epithelial and mesenchymal markers and enhanced cellular plasticity. The authors show that nuclear β-catenin drives increased migration, invasion, proliferation, and metastatic dissemination of HCC cells. Using mouse models, Xu et al. show that these changes all depend on emerin. The authors further demonstrate that nuclear β-catenin contributes to immune evasion by upregulating the expression of poliovirus receptor, thereby reducing the susceptibility of HCC cells to natural-killer cell surveillance. Conversely, restoration of emerin expression in UFMylation-deficient cells reduced nuclear β-catenin availability and reversed both EMT markers and immune-evasive transcriptional signatures and phenotypes. These findings establish the functional role of UFMylation-dependent stabilization of emerin in the regulation of β-catenin in HCC.