UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

Shi, Zhan; Liu, Runkun; Lu, Qiliang; Zeng, Zhi; Liu, Yang; Zhao, Junjun; Liu, Xin; Li, Lijie; Huang, Haohai; Yao, Yingmin; Huang, Dongsheng; Xu, Qiuran

doi:10.7150/ijms.63220

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…The KEGG pathway enrichment analysis suggested that LINC00674 expression was correlated with the mTOR signaling pathway in HCC based on TCGA data. Studies have shown that the activation of mTOR signaling pathway is frequently observed in HCC progression 29 , 30 . mTOR forms a catalytic subunit of two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2 31 .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway

Zhu¹,

Chen²,

Zhao³

et al. 2022

J. Cancer

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The hypoxic tumor microenvironment, a fundamental feature of solid tumors, drives hepatocellular carcinoma (HCC) progression through regulating the transcriptional activities of protein-coding and noncoding genes. However, long noncoding RNA (lncRNA)-mediated HCC progression in hypoxic microenvironment remains largely unknown yet. In this study, we found that LINC00674 was upregulated under hypoxic conditions in a HIF-1-dependent manner, and the occupancy of HIF-1 to HRE of LINC00674 gene promoter was essential for its transcription. In addition, LINC00674 level was increased in HCC cell lines and tissues. Clinically, statistical analysis showed that LINC00674 expression was significantly associated with tumor size, venous infiltration, tumor stage and poor prognosis of HCC. Functionally, loss-of-function assays revealed that LINC00674 knockdown inhibited the migration, proliferation and invasion of HCC cells. Furthermore, LINC00674 silencing prominently repressed the mTOR signaling pathway. LINC00674 overexpression-enhanced HCC cell proliferation, migration and invasion were markedly abolished by an mTOR inhibitor rapamycin. NADPH oxidase 1 (NOX1) was positively regulated by LINC00674 in HCC cells. NOX1 knockdown markedly reversed LINC00674-upregulated the p-mTOR level and HCC cells' malignant behaviors. Finally, we found that LINC00674 knockdown attenuated the growth of HCC cells in vivo . Our finding demonstrated that LINC00674 was a new HIF-1 target gene, and hypoxia-induced LINC00674 exerted a pro-proliferative and pro-metastatic role in HCC, possibly by activating the NOX1/mTOR signaling pathway. This study suggested LINC00674 as a promising therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway

Zhu¹,

Chen²,

Zhao³

et al. 2022

J. Cancer

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“…A positive correlation was reported between the expression of histopathological UBE2O staining and prostate cancer advancement ( 30 ). UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPK/mTOR pathway ( 31 ). UBE2O promotes progression and EMT in head and neck squamous cell carcinoma ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Arborinine from Glycosmis parva leaf extract inhibits clear-cell renal cell carcinoma by inhibiting KDM1A/UBE2O signaling

Feng

Gong

Wang

2022

Food & Nutrition Research

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Background: Arborinine is a natural product isolated from Globigerina parva (G. parva) leaf extract that shows strong anticancer activity with its role in clear-cell renal cell carcinoma (ccRCC) unreported. Objective: We aim to evaluate the role of Arborinine in ccRCC. Design: Arborinine was tested for its effects in ccRCC cell lines in vitro and in silico. Results: Arborinine conferred inhibitory effect to ccRCC cells at reasonable doses. Arborinine showed inhibitory effects on Lysine Demethylase 1A (KDM1A) in ccRCC cells and decreased levels of KDM1A outputs and on epithelial mesenchymal transition (EMT) markers. Arborinine significantly inhibited proliferation, apoptosis, and cell cycle progression and migration of ccRCC cells. Using in silico ChIP analysis and luciferase activity validation, we identified Ubiquitin-conjugating enzyme E2O (UBE2O) as an active transcription target downstream of KDM1A. UBE2O expression was not only correlated with KDM1A expression but also associated with worsened prognosis in ccRCC. Overexpression of UBE2O abrogated cancer-inhibitory effect of Arborinine. Discussion: Arborinine holds promise as an additive in the treatment of ccRCC. Conclusions: We have shown for the first time that Arborinine showed inhibitory effect on ccRCC via KDM1A/UBE2O signaling.

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“…The immunoprecipitation and ubiquitination assays were performed as previously described ( Shi et al, 2021 ). In brief, the cells were incubated with 10 μM MG132 (HY-13259, MedChemExpress, Shanghai, China) for 8 h. HCC cells were treated with IP lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

“…The cell counting kit-8 (CCK-8) kit (Beyotime) and Cell-Light™ EdU Apollo ® 488 In Vitro Imaging Kit (RIBOBIO, Guangzhou, China) were used for HCC cell proliferation determination as previously described ( Shi et al, 2021 ). For colony formation assay, the logarithmic growth cells (1 × 10 3 ) were seeded into 6-well plates and were grown for a period of 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

HIF-1/2α-Activated RNF146 Enhances the Proliferation and Glycolysis of Hepatocellular Carcinoma Cells via the PTEN/AKT/mTOR Pathway

Shen

Wang

Zhu

et al. 2022

Front. Cell Dev. Biol.

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Hypoxia microenvironment, a critical feature of hepatocellular carcinoma, contributes to hepatocarcinogenesis, tumor progression and therapeutic resistance. Hypoxia-inducible factors (HIFs)-activated target genes are the main effectors in hypoxia-induced HCC progression. In this study, we identified ubiquitin E3 ligase ring finger protein 146 (RNF146) as a novel HIFs target gene. Either HIF-1α or HIF-2α knockdown significantly repressed hypoxia-induced RNF146 upregulation in Hep3B and Huh7 cells. TCGA data and our immunohistochemistry analysis consistently revealed the overexpression of RNF146 in HCC tissues. The upregulated expression of RNF146 was also detected in HCC cell lines. The high RNF146 level was correlated with poor clinical features and predicted a shorter overall survival of patients with HCC. RNF146 knockdown suppressed the proliferation, colony formation and glycolysis of HCC cells, but suppressed but RNF146 overexpression promoted these malignant behaviors. Moreover, RNF146 silencing weakened HCC growth in mice. RNF146 inversely regulated phosphatase and tensin homolog (PTEN) protein level, thereby activating the AKT/mechanistic target of rapamycin kinase (mTOR) pathway in HCC cells. MG132 reversed RNF146 overexpression-induced PTEN reduction. RNF146 knockdown decreased the ubiquitination and degradation of PTEN in HCC cells. Therefore, we clarified that PTEN knockdown notably abolished the effects of RNF146 silencing on the AKT/mTOR pathway and Hep3B cells’ proliferation, colony formation and glycolysis. To conclude, our data confirmed that RNF146 was transcriptionally regulated by HIF-1/2α and activated the AKT/mTOR pathway by promoting the ubiquitin proteolysis of PTEN, thereby contributing to HCC progression. RNF146 may be a potential new drug target for anti-HCC.

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UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

Cited by 15 publications

References 42 publications

Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway

Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway

Arborinine from Glycosmis parva leaf extract inhibits clear-cell renal cell carcinoma by inhibiting KDM1A/UBE2O signaling

HIF-1/2α-Activated RNF146 Enhances the Proliferation and Glycolysis of Hepatocellular Carcinoma Cells via the PTEN/AKT/mTOR Pathway

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