HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

Liu, Ningning; Zhang, Jinfang; Yang, Xiaohai; Jiao, Tong; Zhao, Xin; Li, Wenxia; Zhu, Jianhua; Yang, Pu; Jin, Jianping; Peng, Jirun; Li, Zhiwei; Ye, Xin

doi:10.1128/jvi.00340-17

Cited by 41 publications

(46 citation statements)

References 44 publications

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“…Although neddylation is crucial for cullin activation and subsequent degradation of target proteins, such as Smc5/6, by ubiquitination, neddylation may also be involved in other aspects of HBV infection. Indeed, a recent study reported that HBx itself is also modified by NEDD8, and that HBx neddylation enhances HBx protein stability . Thus, although solid data are not available at present, MLN4924 treatment may lead to destabilization of HBx, which may contribute to reduced HBV replication.…”

Section: Discussionmentioning

confidence: 99%

Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

Sekiba¹,

Otsuka²,

Ohno³

et al. 2019

Hepatology

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Hepatitis B virus (HBV)infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitinlike protein for activation, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion: These results indicate that pevonedistat is a promising compound to treat chronic HBV infection. (Hepatology 2019;69:1903-1915).

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Section: Discussionmentioning

confidence: 99%

Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

Sekiba¹,

Otsuka²,

Ohno³

et al. 2019

Hepatology

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“…The chromatin immunoprecipitation (ChIP) assay was performed as previously described . Briefly, cells were lysed in lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

Liu

Yang

et al. 2018

Hepatology

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Recent studies have indicated that a number of long noncoding RNAs (lncRNAs) are dysregulated in hepatocellular carcinoma, while their aberrant expressions are associated with tumorigenesis and poor prognosis. To identify hepatitis B virus (HBV)-related lncRNAs, we used RNA deep sequencing to quantify the abundances of lncRNAs in HepG2 cells and HBV transgenic HepG2-4D14 cells. Here, we demonstrate that lnc-HUR1 is significantly upregulated in HepG2-4D14 cells. We found that HBV-encoded hepatitis B x protein can enhance the transcription of lnc-HUR1. Overexpression of lnc-HUR1 promotes cell proliferation, whereas knockdown of lnc-HUR1 inhibits cell growth. We identified that lnc-HUR1 can interact with p53 and inhibit its transcriptional regulation on downstream genes, such as p21 and B cell lymphoma 2-associated X protein. We generated lnc-HUR1 transgenic mice and performed the partial hepatectomy (PHx) to examine liver regeneration. The data showed that the ratio of liver weight to body weight in lnc-HUR1 transgenic mice is higher than that in wild-type (WT) littermates at day 2 and day 3 following hepatectomy. Consistently, the results of bromodeoxyuridine staining on liver sections following hepatectomy indicate that the ratio of bromodeoxyuridine-positive cells in lnc-HUR1 transgenic mice is significantly higher than that in WT mice, suggesting that lnc-HUR1 promotes cell proliferation during liver regeneration. Next, we performed the experiment of diethylnitrosamine-induced tumorigenesis. The data demonstrate that tumor number in lnc-HUR1 transgenic mice is higher compared with control mice, indicating that lnc-HUR1 enhances diethylnitrosamine-induced tumorigenesis. Conclusion: We reveal that HBV-upregulated lnc-HUR1 promotes cell proliferation and tumorigenesis by interacting with p53 to block downstream gene transcription. Our findings suggest that lnc-HUR1 plays an important role in HBV-related hepatocellular carcinoma development and may serve as a therapeutic marker for hepatocellular carcinoma. (Hepatology 2018; 00:000-000).

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“…Based on a previous report 39 , tumor growth in mice was performed. In brief, 1 × 10 7 stably transfected HepG2 and Hep3B cells were transplanted into the body of 6-week-old BALB/c nude mice (Slac Laboratory Animal Center, Shanghai, China) via subcutaneous injection.…”

Section: In Vivo Tumor Growth Assaymentioning

confidence: 99%

PITPNA-AS1 abrogates the inhibition of miR-876-5p on WNT5A to facilitate hepatocellular carcinoma progression

Sun

Zhang

et al. 2019

Cell Death Dis

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LncRNA PITPNA-AS1 was a newly identified lncRNA which has never been studied in cancers. Whether PITPNA-AS1 participated in the development of hepatocellular carcinoma (HCC) is obscure. Given the coaction of lncRNAs and miRNAs to carcinogenesis, the purpose of the present research is to inquire how PITPNA-AS1 affects HCC progression. Firstly, PITPNA-AS1 was observed to be heightened in HCC tissues. Then function assays proved that overexpressing or silencing PITPNA-AS1 could manipulate the proliferation and motility of HCC cells. Besides, PITPNA-AS1 was located in the cytoplasm. Among the candidate miRNAs of PITPNA-AS1, miR-876-5p was an obvious target. Moreover, mechanism experiments validated that PITPNA-AS1 modulated WNT5A expression by targeting miR-876-5p. Rescue experiments affirmed that WNT5A silencing rescued the miR-876-5p suppression-induced cellular processes in PITPNA-AS1-silenced Hep3B cells. And in vivo experiments determined that PITPNA-AS1 regulated HCC progression in vivo via miR-876-5p/WNT5A pathway. In conclusion, this work shed lights on the modulatory mechanism of PITPNA-AS1/miR-876-5p/WNT5A axis in HCC, which might be pivotal for exploring effective diagnostic biomarkers and treatment strategies for HCC patients.

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HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

Cited by 41 publications

References 44 publications

Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

Pevonedistat, a Neuronal Precursor Cell‐Expressed Developmentally Down‐Regulated Protein 8–Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus

Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity

PITPNA-AS1 abrogates the inhibition of miR-876-5p on WNT5A to facilitate hepatocellular carcinoma progression

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