Neddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis

Xie, Mingjie; Guo, Huiting; Lou, Guohua; Yao, Jiping; Liu, Yanning; Sun, Yi; Zhou, Yang; Zheng, Min

doi:10.1111/jcmm.16137

Cited by 29 publications

(27 citation statements)

References 61 publications

(144 reference statements)

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“…[56][57][58] Among them, MLN4924 has been shown to have anti-HBV activity. 59,60 Therefore, these inhibitors have potential for a novel anti-HBV therapy. Further studies are necessary to understand how neddylation is involved in HBV life cycles.…”

Section: Discussionmentioning

confidence: 99%

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Deneddylation by SENP8 restricts hepatitis B virus propagation

Chen

Suzuki

Itoh

et al. 2021

Microbiology and Immunology

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Proteins newly synthesized from messenger RNA undergo Posttranslational modifications (PTMs) such as phosphorylation, glycosylation, methylation, and ubiquitination. These PTMs have important roles in protein stability, localization, and conformation and have been reported to be involved in hepatitis B virus (HBV) propagation. Although ubiquitination plays an essential role in HBV life cycles, the involvement of ubiquitin-like proteins (UBLs) in HBV life cycles has been understudied. Through comprehensive gain-and loss-of-function screening of UBLs, we observed that neddylation, a PTM in which neural precursor cell, expressed developmentally downregulated 8 (NEDD8) is conjugated to substrate proteins, was required for efficient HBV propagation. We also found that overexpression of sentrinspecific protease 8 (SENP8), which cleaves conjugated NEDD8, suppressed HBV propagation. Further, the catalytic activity of SENP8 was required for the suppression of HBV propagation. These results indicated that the reduction of neddylation negatively regulated HBV propagation. In addition, we demonstrated that suppression of HBV propagation via SENP8 overexpression was independent of hepatitis B protein X (HBx) and HBV promoter activity. Therefore, our data suggested that neddylation plays an important role in the late stages of HBV life cycles. K E Y W O R D S hepatitis B virus, NEDD8, neddylation, SENP8 1 | INTRODUCTION Hepatitis B virus (HBV) infection is strongly associated with acute and chronic liver disease and is a major global health problem. The World Health Organization estimates that around 2 billion people have been infected with HBV and that there over 240 million chronically infected patients worldwide. 1 Chronic HBV infection is a risk factor for developing liver cirrhosis and hepatocellular carcinoma. Although reverse transcriptase inhibitors and interferon alpha are approved for HBV treatment and can suppress viral replication, these strategies are limited, and viral cure is rarely achieved. 2 Therefore, the development of novel treatment approaches for viral infections is required. A number of cellular factors are reported to be involved in HBV propagation. For example, cyclin-dependent kinase 4 inhibitor C (CDKN2C) expression supports the transcription of HBV covalently closed circular DNA. 3 The interaction between hepatitis B core antigen (HBc) and serine/arginine-rich splicing factor 10 (SRSF10) is involved in HBV replication. 4 We also previously reported that hepatitis B protein X (HBx) interacts with Jumonji-C (JmjC)

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Section: Discussionmentioning

confidence: 99%

“…TAS4464, MLN4924, and LP0040 were reported as inhibitors of the Nedd8‐activating enzyme 56–58 . Among them, MLN4924 has been shown to have anti‐HBV activity 59,60 . Therefore, these inhibitors have potential for a novel anti‐HBV therapy.…”

Section: Discussionmentioning

confidence: 99%

Deneddylation by SENP8 restricts hepatitis B virus propagation

Chen

Suzuki

Itoh

et al. 2021

Microbiology and Immunology

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“…NEDDylation-dependent reduction of ubiquitination and subsequent degradation of HBx by E3 Ligases, such as Siah-1, may account for the increased stability of this viral protein. MLN4924 (pevonedistat), a NEDD8-activating enzyme inhibitor, has been shown to impede HBV replication by reducing cullin[ 147 ] and HBx NEDDylation[ 146 ]. In addition, MLN4924 promotes upregulation of phosphorylated extracellular signal-regulated kinases (ERKs) resulting in reduced HNF1α, HNF4α and C/EBPα transcription factor levels[ 147 ], which are known activators of HBV transcription.…”

Section: Viral Factors As Epigenetic Regulatorsmentioning

confidence: 99%

“…MLN4924 (pevonedistat), a NEDD8-activating enzyme inhibitor, has been shown to impede HBV replication by reducing cullin[ 147 ] and HBx NEDDylation[ 146 ]. In addition, MLN4924 promotes upregulation of phosphorylated extracellular signal-regulated kinases (ERKs) resulting in reduced HNF1α, HNF4α and C/EBPα transcription factor levels[ 147 ], which are known activators of HBV transcription. Overall, the maintenance of persistent HBV infection by HBx contributes to HCC, by inducing host epigenetic modifications implicated in cancer.…”

Section: Viral Factors As Epigenetic Regulatorsmentioning

confidence: 99%

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Singh

Kairuz

Arbuthnot

et al. 2021

WJG

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Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.

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“…Osteosarcoma (OS) is the most aggressive bone malignancy in children and adolescents, resulting in significant morbidity and mortality [ 1 ]. Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the overall survival rates of OS have reached a plateau [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy

Yang

Liang

et al. 2021

J Nanobiotechnol

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Background Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. Methods and results A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. Conclusion All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.

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Neddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 29 publications

References 61 publications

Deneddylation by SENP8 restricts hepatitis B virus propagation

Deneddylation by SENP8 restricts hepatitis B virus propagation

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy

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