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SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.

ABSTRACT: SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.

SUBMITTER: Liu H

PROVIDER: S-EPMC5446059 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.

Liu Hong H Ma Yan Y He Hong-Wei HW Zhao Wu-Li WL Shao Rong-Guang RG

Autophagy 20170501 5

SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. ...[more]

PMID: 28521610

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Project description:BackgroundDrug resistance is a major contributing factor to chemotherapy failure in hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying the chemoresistance of HCC remains unknown.MethodsHepG2 cells were incubated with different concentrations of 5-fluorouracil (5-FU), and the Cell Counting Kit-8 assay was used to test the cell survival rate. The expression level of structural maintenance of chromosome 4 (SMC4) in drug-resistant cells was analyzed by real-time quantitative polymerase chain reaction (PCR) and western blotting. To assess autophagy, immunofluorescence was applied to detect the light chain 3 beta (LC3B) level in HepG2/5-FU cells. To further study the upstream regulation of miR (microRNA)-219/SMC4, a gene chip assay was performed. A luciferase reporter assay was used to determine whether long non-coding RNA-XIST (lncRNA-XIST) functions as a competitive endogenous RNA (ceRNA) for miR-219. Cellular proliferation was evaluated using MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-2,5-di-phenytetrazoliumromide] and colony formation assays, wound healing and invasion assays were performed to study the invasion and migration ability of the cells, and flow cytometry assays were carried out to evaluate cell apoptosis.ResultsIn the present study, we established a drug-resistant hepatoma cell line named HepG2/5-FU. We confirmed that SMC4 may play an important role in hepatoma cell autophagy and could promote autophagy to increase the drug resistance of hepatoma cells. We also demonstrated that lncRNA-XIST may competitively bind to miR-219 by acting as a miRNA sponge, thereby preventing miR-219 from effectively reducing the expression of SMC4 and further affecting the autophagy and drug resistance of hepatoma cells via the adenosine 5'-monophosphate (AMP)-activated protein kinase/mechanistic target of rapamycin (AMPK/mTOR) pathway.ConclusionsOur study suggests that SMC4 may be a potential marker of a poor HCC response to chemotherapy and a novel therapeutic target for HCC chemotherapy.

Project description:Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation and development of several B-cell lymphomas particularly those are generated in an immuno-compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family oncoproteins-EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked polyubiquitinated, colocalized with the autophagy-lysosomal fraction in the cytoplasm and participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We further show that the degradation signal is present at the first 50 residues of the N-terminal region of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral oncoprotein, induces apoptotic cell death and increases transcriptional activation of both latent and lytic gene expression which further promotes viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV associated B-cell lymphomas, where EBNA3C is expressed.

Dataset Information

SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.

Publications

SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.

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