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Accumulating evidences have indicated that PDZ and LIM domain 2 (PDLIM2) served as a critical tumor suppressor in hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying its diminished protein expression in HCC pathogenesis remain poorly characterized. In this study, we revealed that PDLIM2 downregulation enhanced malignant proliferation of HCC cells. Mechanistically, PDLIM2 interacted with tripartite motif-containing protein 27 (TRIM27), facilitating its K27-linked polyubiquitination-mediated proteasomal degradation. This posttranslational modification consequently attenuated STAT3 signaling activation. Furthermore, we elucidated that pre-B-cell leukemia transcription factor-interacting protein 1 (PBXIP1) overexpression in HCC enhanced the polyubiquitination of PDLIM2 through the ubiquitin‒proteasome system, which was responsible for PDLIM2 protein destabilization in HCC. Collectively, our findings reveal that the PBXIP1-mediated posttranslational regulation of PDLIM2 contributes to its tumor-suppressive effects via the modulation of the TRIM27/STAT3 oncogenic axis during HCC progression.