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 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+, poh1 f/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.

Caveolin-1 function at the plasma membrane and in intracellular compartments in cancer

“…Alternatively, EGF treatment induces caveola-dependent endocytosis of plasma membrane E-cadherin/β-catenin complex, disrupts cell-cell Non-membrane-bounded organelle + Cell projection + Joshi et al [71] Cytoplasmic vesicle + Fridolfsson et al [44] Lipid particle + Fridolfsson et al [44] contacts, downregulates E-cadherin as well as CAV1, and thereby promotes invasion of cancer cells [99]. Moreover, CAV1 has been proposed to inhibit TGF-β signaling, via caveolae/membrane raft-mediated endocytosis and lysosomal degradation of TGF-β receptors [28,175]. On the one hand, CAV1 interacts with TGF-β receptors, abolishing their interaction with SMAD proteins and downstream events [28].…”

Immune prognostic implications of PSMD14 and its associated genes signatures in hepatocellular carcinoma

“…The deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14, RPN11 or POH1), belongs to the JAMM domain metalloprotease family of DUBs and is an important part of 19S regulatory cap in 26S proteasome [5]. PSMD14 has been confirmed to play vital roles in gene ontology and related pathway, including protein stability [6], tumour formation [7], transcriptional regulation [8], double-strand DNA break repair [9], senescence [10], apoptosis and resistance [11], growth and metastasis [5], BMP6 signaling [6], TGF-β signaling [8]. Recently, PSMD14 has been overexpressed in many human cancers, such as HCC, colorectal cancer, multiple myeloma, esophageal squamous cell carcinoma and breast cancer, which it This is related to the poor prognosis of the patients [5,6,[11][12][13].…”

“…Similarly, PSMD14 inhibits degradation of GRB2 by deubiquitinating this oncoprotein and stabilizing GRB2, which it enhances hepatocellular carcinoma growth and metastasis [5]. POH1 deubiquitinates the TGF-β receptors and CAV1, contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis, which it negatively regulates lysosome pathway-mediated turnover of TGF-β receptors [8]. However, other mechanisms of the contribution of PSMD14 in the progression of HCC remained to be further explored.…”

Immune Prognostic Implications of PSMD14 and Its Associated Genes Signatures in Hepatocellular Carcinoma

“…The deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14, RPN11 or POH1), belongs to the JAMM domain metalloprotease family of DUBs and is an important part of 19S regulatory cap in 26S proteasome (6). PSMD14 has been con rmed to play vital roles in gene ontology and related pathway, including protein stability (7), tumour formation (8), transcriptional regulation (9), double-strand DNA break repair (10), senescence (11), apoptosis and resistance (12), growth and metastasis (6), BMP6 signaling (7), TGF-β signaling (9). Recently, it has been found that PSMD14 is overexpressed in many human cancers, such as HCC, colorectal cancer, multiple myeloma, esophageal squamous cell carcinoma and breast cancer, which are related to the poor prognosis of the patients (6,7,(12)(13)(14).…”

“…PSMD14 stabilizes and inhibits the degradation of GRB2 through deubiquitination, which is an oncoprotein enhances hepatocellular carcinoma growth and metastasis (6). POH1 deubiquitinates the TGF-β receptors and CAV1, contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis, which it negatively regulates lysosome pathway-mediated turnover of TGF-β receptors (9). Other mechanisms of the contribution of PSMD14 in the progression of HCC remains to be further explored.…”