Deubiquitylase OTUD6B Governs pVHL Stability in an Enzyme‐Independent Manner and Suppresses Hepatocellular Carcinoma Metastasis

Liu, Xinxin; Zhang, Xiaoli; Peng, Zhiqiang; Li, Chunnan; Wang, Ze; Wang, Chanjuan; Deng, Zhikang; Wu, Bo; Cui, Yu; Wang, Zhanxin; Chu, Chun-Ping; Zheng, Ming‐Hua; Zhang, Lingqiang

doi:10.1002/advs.201902040

Cited by 32 publications

(35 citation statements)

References 55 publications

(73 reference statements)

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“…This post-translational modification of HIF-1α leads to its recognition by pVHL and tags HIF-1α for degradation [5,43]. pVHL is coupled with Rbx1, cullin-2, elongin B and elongin C to assemble E3 ubiquitin ligase complex, which mediates ubiquitin-proteasome degradation of HIF-1α [44]. However,…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

2021

PLoS ONE

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The mortality rate of ovarian cancer is increasing and the role of hypoxia inducible factor-1α (HIF-1α) in tumor progression has been confirmed. von Hippel-Lindau tumor suppressor protein (pVHL) binds HIF-1α and mediates proteasome degradation of HIF-1α. Besides, histone deacetylase inhibitor (HDACi) mitigates tumor growth via targeting HIF-1α, whereas underlying mechanism still requires investigation. In this research, we exposed ovarian cancer cell lines OV-90 and SKOV-3 to escalating concentrations of HDACi LBH589. As a result, cell viability was significantly suppressed and expression of HIF-1α was remarkably reduced along with decreased levels of signal molecules, including phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) (P = 0.000). Interestingly, pVHL was expressed in a notably declining tendency (P = 0.000). Chaperone heat shock protein-70 (HSP70) was expressed in an ascending manner, whereas expression of chaperonin TCP-1α was reduced clearly (P = 0.000). Besides, co-inhibition of pVHL plus HDAC did not contribute to a remarkable difference in HIF-1α expression as compared with single HDAC inhibition. Furthermore, both cell lines were transfected with plasmids of VHL plus VHL binding protein-1 (VBP-1). Consequently, the expression of HIF-1α as well as lactate dehydrogenase-A (LDHA) was remarkably decreased (P = 0.000). These findings indicate HDACi may repress expression of HIF-1α via inhibiting PI3K and GSK3β and promote degradation of HIF-1α via HSP70, independent of pVHL. Additionally, a sophisticated network of HDAC and chaperones may involve in pVHL quality control.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

2021

PLoS ONE

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“…Second, we investigated the correlations between key genes and prognosisrelated cells. Third, from the GEPIA and TIMER databases, we detected correlations between the key genes and biomarkers of prognosis-related cells reported by previous research (CD11B, CD33 for MDSCs, CD34, CD117 for HSCs, CD31, CD105 for ECs) [36][37][38] and hypoxic microenvironment-forming factors such as hypoxiainducible factor 1α (HIF1A) and VEGFA [39]. The results were visualized using the corrplot R package.…”

Section: Analyses Of Key Gene-tumor Microenvironment (Tme)mentioning

confidence: 99%

Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma

Chen

Feng

Zhou

et al. 2021

BioMed Research International

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Hepatocellular carcinoma (HCC) is an aggressive cancer type with poor prognosis; thus, there is especially necessary and urgent to screen potential prognostic biomarkers for early diagnosis and novel therapeutic targets. In this study, we downloaded target data sets from the GEO database, and obtained codifferentially expressed genes using the limma R package and identified key genes through the protein–protein interaction network and molecular modules, and performed GO and KEGG pathway analyses for key genes via the clusterProfiler package and further determined their correlations with clinicopathological features using the Oncomine database. Survival analysis was completed in the GEPIA and the Kaplan–Meier plotter database. Finally, correlations between key genes, cell types infiltrated in the tumor microenvironment (TME), and hypoxic signatures were explored based on the TIMER database. From the results, 11 key genes related to the cell cycle were determined, and high levels of these key genes’ expression were focused on advanced and higher grade status HCC patients, as well as in samples of TP53 mutation and vascular invasion. Besides, the 11 key genes were significantly associated with poor prognosis of HCC and also were positively related to the infiltration level of MDSCs in the TME and the HIF1A and VEGFA of hypoxic signatures, but a negative correlation was found with endothelial cells (ECs) and hematopoietic stem cells. The result determined that 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) could play a vital role in the pathogenesis of HCC, drive the communication between tumor cells and the TME, and act as probably promising diagnostic, therapeutic, and prognostic biomarkers in HCC patients.

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“…The stabilized pVHL recognizes and degrades hydroxylated or SUMOylated HIF-1α in hypoxia. As a result, OTUD6B increases the stability of pVHL to prevent metastasis of hepatocellular carcinoma [126,127].…”

Section: Otud6bmentioning

confidence: 99%

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

Kim

Baek

2021

IJMS

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Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin–proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

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Deubiquitylase OTUD6B Governs pVHL Stability in an Enzyme‐Independent Manner and Suppresses Hepatocellular Carcinoma Metastasis

Abstract: Keywordsdeubiquitylase, hepatocellular carcinoma metastasis, hypoxia inducible factor, OTUD6B, von Hippel-Lindau

Cited by 32 publications

References 55 publications

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system

Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

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