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

EBioMedicine. 2019 Mar;41:320-332. doi: 10.1016/j.ebiom.2019.01.058. Epub 2019 Feb 7.

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: Associations of deubiquitinase POH1 with TGF-β 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-β receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were 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-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.

Keywords: Hepatocellular carcinoma.; POH1; TGF-β receptor; TGF-β signaling.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Caveolin 1 / metabolism*
  • Cell Line, Tumor
  • Down-Regulation
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Prognosis
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitination

Substances

  • Caveolin 1
  • PSMD14 protein, human
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Trans-Activators
  • Transforming Growth Factor beta
  • Proteasome Endopeptidase Complex