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

Background: Hyper-activation of TGF-beta signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-beta pathway in HCC, especially at the posttranslational level, are not well understood. Methods: Associations of deubiquitinase POH1 with TGF-beta signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-beta receptors (TGFBR1 and TGFBR2) and the activation of downstreameffectorswere tested by western blotting. Primary mouse liver tissues from polyinosinic: polycytidylic acid (poly I: C)-treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-beta receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice. Findings: Herewe show that POH1 is a critical regulator of TGF-beta signaling and promotes tumormetastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-beta response, metastatic potential and outcomes, reveal that POH1 expression positively correlateswith activities of TGF-beta signaling in tumors andwithmalignant disease progression. Functionally, POH1 intensifies TGF-beta signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-beta receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-beta receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-beta receptors. Conclusion: Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-beta signaling hyperactivation and aggressive progression in HCC. (c) 2019 Published by Elsevier B. V. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).