Hepatitis B virus X protein–elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis

Gao, Yuen; Feng, Jinyan; Yang, Guang; Zhang, Shuqin; Liu, Yunxia; Bu, Yanan; Sun, Mingming; Zhao, Man; Chen, Fuquan; Zhang, Weiying; Ye, Lihong; Zhang, Xiaodong

doi:10.1002/hep.29316

Cited by 62 publications

(77 citation statements)

References 35 publications

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“…Because a reduction in viral transcription would lead to a reduction in new cccDNA formation and to the destabilization of cccDNA, we determined the changes in HBV cccDNA levels after MLN4924 treatment. We extracted cccDNA specifically from cells using the Hirt extraction method and subsequent T5 exonuclease treatment, and precisely measured cccDNA levels by ddPCR .…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Although HBV infection is an important public health problem worldwide (39), the mechanisms of HBV pathogenesis are largely unknown. The aim of this study is to reveal the mechanism underlying the regulation of HBV replication.…”

Section: Discussionmentioning

confidence: 99%

“…7D), revealing that HoxA10 represses X promoter activation. The X promoter regulates HBx gene transcription, which potentiates HBV replication, regulates HBV oncogenicity, and affects multiple cellular functions (38)(39)(40)(41). We constructed the X/EnhI promoter and its five promoter-truncated mutants and then subcloned these constructs into the pGL3-Basic vector to generate six reporters (Fig.…”

Section: Hoxa10 Attenuates Mapk Activation and Hbv Replicationmentioning

confidence: 99%

HoxA10 Facilitates SHP-1-Catalyzed Dephosphorylation of p38 MAPK/STAT3 To Repress Hepatitis B Virus Replication by a Feedback Regulatory Mechanism

Yang

Zhang

et al. 2019

J Virol

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Hepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BALB/c mice. Interestingly, we show that during early HBV infection, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were activated to facilitate HBV replication; however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK, recruits SH2containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to the HBV enhancer element I (EnhI)/X promoter, competes with STAT3 for binding of the promoter, and thereby represses HBV transcription. Taken together, these results show that HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication, and HoxA10 binds to the EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in terms of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection. IMPORTANCE Two billion people have been infected with HBV worldwide; about 240 million infected patients developed chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Moreover, HoxA10 competes with STAT3 for binding of the HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and provides new insights into the development of potential agents to control HBV infection. KEYWORDS hepatitis B virus infection and pathogenesis, homeobox protein A10, J. 2019. HoxA10 facilitates SHP-1-catalyzed dephosphorylation of p38 MAPK/STAT3 to repress hepatitis B virus replication by a feedback regulatory mechanism...

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“…The miR-155 seed site in ZHX2 3 0 UTR was deleted for the 3 0 UTR-del mut. [36][37][38][39][40][41] Here, we have identified HBxmediated inhibition of ZHX2 via miR-155 as another possible mechanism by which HBV influences HCC progression (Fig. The pRL-TK plasmid was transfected into all cells as Renilla luciferase control.…”

Section: Discussionmentioning

confidence: 99%

“…34,35 One of the predominant HBV proteins in HCC is HBx, which activates oncogenes, leads to epigenetic modifications, modulates miRNAs and long non-coding RNAs and affects proliferation, apoptosis, metabolism, chemotherapy resistance and metastasis. [36][37][38][39][40][41] Here, we have identified HBxmediated inhibition of ZHX2 via miR-155 as another possible mechanism by which HBV influences HCC progression (Fig. 6c).…”

Section: Discussionmentioning

confidence: 99%

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

Song

Tan

et al. 2018

Intl Journal of Cancer

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Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were found in HBV-positive tumors, livers of HBV transgenic mice and HBx-overexpressing hepatoma cell lines. MiR-155 overexpression reduced ZHX2 levels via miR-155 seed sites in the ZHX2 3'UTR, whereas blocking miR-155 levels led to increased ZHX2 levels. Taken together, our data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC.

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Hepatitis B virus X protein–elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis

Cited by 62 publications

References 35 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

HoxA10 Facilitates SHP-1-Catalyzed Dephosphorylation of p38 MAPK/STAT3 To Repress Hepatitis B Virus Replication by a Feedback Regulatory Mechanism

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

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