POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1

Abstract

BACKGROUND: Hyper-activation of TGF-β signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-β pathway in HCC, especially at the post-translational level, are not well understood. METHODS: mice and control mice were used to detect the TGF-β receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice. FINDINGS: Here we show that POH1 is a critical regulator of TGF-β signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-β response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-β signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-β signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-β receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-β receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-β receptors. CONCLUSION: Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-β signaling hyperactivation and aggressive progression in HCC.