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Neddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis
dc.contributor.authorXie, Mingjie
dc.contributor.authorGuo, Huiting
dc.contributor.authorLou, Guohua
dc.contributor.authorYao, Jiping
dc.contributor.authorLiu, Yanning
dc.contributor.authorSun, Yi
dc.contributor.authorYang, Zhenggang
dc.contributor.authorZheng, Min
dc.date.accessioned2021-02-04T21:52:33Z
dc.date.available2022-02-04 16:52:32en
dc.date.available2021-02-04T21:52:33Z
dc.date.issued2021-01
dc.identifier.citationXie, Mingjie; Guo, Huiting; Lou, Guohua; Yao, Jiping; Liu, Yanning; Sun, Yi; Yang, Zhenggang; Zheng, Min (2021). "Neddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis." Journal of Cellular and Molecular Medicine (2): 840-854.
dc.identifier.issn1582-1838
dc.identifier.issn1582-4934
dc.identifier.urihttps://hdl.handle.net/2027.42/166239
dc.description.abstractHepatitis B virus (HBV) infection is a major public health problem. The high levels of HBV DNA and HBsAg are positively associated with the development of secondary liver diseases, including hepatocellular carcinoma (HCC). Current treatment with nucleos(t)ide analogues mainly reduces viral DNA, but has minimal, if any, inhibitory effect on the viral antigen. Although IFN reduces both HBV DNA and HBsAg, the serious associated side effects limit its use in clinic. Thus, there is an urgent demanding for novel anti‐HBV therapy. In our study, viral parameters were determined in the supernatant of HepG2.2.15 cells, HBV‐expressing Huh7 and HepG2 cells which transfected with HBV plasmids and in the serum of HBV mouse models with hydrodynamic injection of pAAV‐HBV1.2 plasmid. RT‐qPCR and Southern blot were performed to detect 35kb mRNA and cccDNA. RT‐qPCR, Luciferase assay and Western blot were used to determine anti‐HBV effects of MLN4924 and the underlying mechanisms. We found that treatment with MLN4924, the first‐in‐class neddylation inhibitor currently in several phase II clinical trials for anti‐cancer application, effectively suppressed production of HBV DNA, HBsAg, 3.5kb HBV RNA as well as cccDNA. Mechanistically, MLN4924 blocks cullin neddylation and activates ERK to suppress the expression of several transcription factors required for HBV replication, including HNF1α, C/EBPα and HNF4α, leading to an effective blockage in the production of cccDNA and HBV antigen. Our study revealed that neddylation inhibitor MLN4924 has impressive anti‐HBV activity by inhibiting HBV replication, thus providing sound rationale for future MLN4924 clinical trial as a novel anti‐HBV therapy.
dc.publisherPublic Health Foundation
dc.publisherWiley Periodicals, Inc.
dc.subject.otherMAPK
dc.subject.otherneddylation
dc.subject.otherMLN4924
dc.subject.othertranscription factors
dc.subject.otherHBV
dc.titleNeddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/166239/1/jcmm16137_am.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/166239/2/jcmm16137.pdf
dc.identifier.doi10.1111/jcmm.16137
dc.identifier.doihttps://dx.doi.org/10.7302/162
dc.identifier.sourceJournal of Cellular and Molecular Medicine
dc.identifier.citedreferenceXia Y, Cheng X, Li Y, Valdez K, Chen W, Liang TJ. Hepatitis B virus deregulates the cell cycle to promote viral replication and a premalignant phenotype. J Virol. 2018; 92 ( 19 ): e00722‐18.
dc.identifier.citedreferenceMurphy C, Xu Y, Li F, et al. Hepatitis B virus X protein promotes degradation of SMC5/6 to enhance HBV replication. Cell Rep. 2016; 16 ( 11 ): 2846 ‐ 54.
dc.identifier.citedreferenceNakabayashi H, Taketa K, Miyano K, Yamane T, Sato J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Can Res. 1982; 42 ( 9 ): 3858 ‐ 63.
dc.identifier.citedreferenceSells MA, Chen ML, Acs G. Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci. 1987; 84: 1005 ‐ 9.
dc.identifier.citedreferenceHuang LR, Wu HL, Chen PJ, Chen DS. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci U S A. 2006; 103 ( 47 ): 17862 ‐ 7.
dc.identifier.citedreferenceGuidotti LG, Matzke B, Schaller H, Chisari FV. High‐level hepatitis B virus replication in transgenic mice. J Virol. 1995; 69 ( 10 ): 6158 ‐ 69.
dc.identifier.citedreferenceYu J, Huang W‐L, Xu Q‐G, et al. Overactivated neddylation pathway in human hepatocellular carcinoma. Cancer Med. 2018; 7 ( 7 ): 3363 ‐ 3372.
dc.identifier.citedreferenceKo C, Shin YC, Park WJ, Kim S, Kim J, Ryu WS. Residues Arg703, Asp777, and Arg781 of the RNase H domain of hepatitis B virus polymerase are critical for viral DNA synthesis. J Virol. 2014; 88 ( 1 ): 154 ‐ 63.
dc.identifier.citedreferenceGuo HJD, Zhou T, Cuconati A, Block TM, Guo JT. Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis Bvirus: an intermediate of covalently closed circular DNA formation. J Virol. 2007; 81: 12472 ‐ 84.
dc.identifier.citedreferenceYan H, Zhong GC, Xu GW, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012; 1: e00049.
dc.identifier.citedreferenceLadner SK, Otto MJ, Barker CS, et al. Inducible expression of human hepatitis B virus (HBV) in stably transfected hepatoblastoma cells: a novel system for screening potential inhibitors of HBV replication. Antimicrob Agents Chemother. 1997; 41 ( 8 ): 1715 ‐ 20.
dc.identifier.citedreferenceDelaney WET, Ray AS, Yang H, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006; 50 ( 7 ): 2471 ‐ 7.
dc.identifier.citedreferenceChong CL, Chen ML, Wu YC, et al. Dynamics of HBV cccDNA expression and transcription in different cell growth phase. J Biomed Sci. 2011; 18: 96.
dc.identifier.citedreferenceZhou X, Tan M, Nyati MK, Zhao Y, Wang G, Sun Y. Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo. Proc Natl Acad Sci U S A. 2016; 113 ( 21 ): E2935 ‐ 44.
dc.identifier.citedreferenceWu L, Wang W, Zhang X, Zhao X, Yu G. Anti‐HBV activity and mechanism of marine‐derived polyguluronate sulfate (PGS) in vitro. Carbohyd Polym. 2016; 143: 139 ‐ 48.
dc.identifier.citedreferenceZhao Z, Hong W, Zeng Z, et al. Mucroporin‐M1 inhibits hepatitis B virus replication by activating the mitogen‐activated protein kinase (MAPK) pathway and down‐regulating HNF4alpha in vitro and in vivo. J Biol Chem. 2012; 287 ( 36 ): 30181 ‐ 90.
dc.identifier.citedreferenceHatzis P, Kyrmizi I, Talianidis L. Mitogen‐activated protein kinase‐mediated disruption of enhancer‐promoter communication inhibits hepatocyte nuclear factor 4 alpha expression. Mol Cell Biol. 2006; 26 ( 19 ): 7017 ‐ 29.
dc.identifier.citedreferenceSekiba K, Otsuka M, Ohno M, et al. Pevonedistat, a first‐in‐class NEDD8‐activating enzyme inhibitor, is a potent inhibitor of hepatitis B virus. Hepatology. 2018; 69 ( 5 ): 1903 – 1915.
dc.identifier.citedreferenceXie MJ, Yang F, Yang ZG, Shui LY, Zheng M. Targeting Neddylation, a Potential Strategy in Anti‐HBV Therapy. Hepatology. 2018; 68: 235a ‐ 6a.
dc.identifier.citedreferenceQuasdorff M, Protzer U. Control of hepatitis B virus at the level of transcription. J Viral Hepatitis. 2010; 17 ( 8 ): 527 ‐ 36.
dc.identifier.citedreferencePan Y, Ke Z, Ye H, et al. Saikosaponin C exerts anti‐HBV effects by attenuating HNF1alpha and HNF4alpha expression to suppress HBV pgRNA synthesis. Inflamm Res. 2019; 68 ( 12 ): 1025 ‐ 34.
dc.identifier.citedreferenceShu Shi ML, Xi J, Liu H, et al. Sex‐determining region Y box 4 (SOX4) suppresses Hepatitis B virus replication by inhibiting hepatocyte nuclear factor 4α expression. Antivir Res. 2020; 176: 104745.
dc.identifier.citedreferenceRaney AK, Easton AJ, Milich DR, McLachlan A. Promoter‐specific transactivation of hepatitis B virus transcription by a glutamine‐ and proline‐rich domain of hepatocyte nuclear factor 1. J Virol. 1991; 65 ( 11 ): 5774 ‐ 81.
dc.identifier.citedreferenceZhou DX, Yen TSB. The ubiquitous transcription factor Oct‐1 and the liver‐specific factor Hnf‐1 are both required to activate transcription of a hepatitis‐B virus promoter. Mol Cell Biol. 1991; 11 ( 3 ): 1353 ‐ 9.
dc.identifier.citedreferenceWang ML, Wu X, Wang YZ. HNFl is critical for the liver‐specific function of HBV enhancer II. Virology. 1998; 149: 99 ‐ 108.
dc.identifier.citedreferenceZi‐Yu Wang Y‐QL, Guo Z‐W, Zhou X‐H, Mu‐Dan LU, Xue T‐C, Gao BO. ERK1/2‐HNF4α axis is involved in epigallocatechin‐3‐gallate inhibition of HBV replication. Acta Pharmacol Sin. 2020; 41 ( 2 ): 278 ‐ 85.
dc.identifier.citedreferenceLijie Li YL. Zhiqi Xiong, Wangqin Shu, Yuanyuan Yang, Zhiwei Guo, Bo Gao FoxO4 inhibits HBV core promoter activity through ERK‐mediated downregulation of HNF4α. Antivir Res. 2019; 170: 104568.
dc.identifier.citedreferenceZheng YY, Li J, Johnson DL, Ou JH. Regulation of hepatitis B virus replication by the Ras‐mitogen‐activated protein kinase signaling pathway. J Virol. 2003; 77 ( 14 ): 7707 ‐ 12.
dc.identifier.citedreferenceMao H, Sun Y. Neddylation‐independent activities of MLN4924. Adv Exp Med Biol. 2020; 1217: 363 ‐ 72.
dc.identifier.citedreferencePolaris OC. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The lancet Gastroenterol Hepatol. 2018; 3 ( 6 ): 383 ‐ 403.
dc.identifier.citedreferenceFiel MI. Pathology of chronic hepatitis B and chronic hepatitis C. Clin Liver Dis. 2010; 14 ( 4 ): 555 ‐ 575.
dc.identifier.citedreferenceNannini P, Sokal EM. Hepatitis B: changing epidemiology and interventions. Arch Dis Child. 2017; 102 ( 7 ): 676 ‐ 680.
dc.identifier.citedreferenceChisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathologie‐biologie. 2010; 58 ( 4 ): 258 ‐ 266.
dc.identifier.citedreferenceMcMahon BJ. Natural history of chronic hepatitis B. Clin Liver Dis. 2010; 14 ( 3 ): 381 ‐ 396.
dc.identifier.citedreferenceHamborsky JKA, Wolfe S. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine‐preventable diseases. Washington DC: Public Health Foundation; 2015; 149 ‐ 174.
dc.identifier.citedreferenceLok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. J Hepatol. 2017; 67 ( 4 ): 847 ‐ 861.
dc.identifier.citedreferenceMueller H, Wildum S, Luangsay S, et al. A novel orally available small molecule that inhibits hepatitis B virus expression. J Hepatol. 2018; 68 ( 3 ): 412 ‐ 420.
dc.identifier.citedreferencePant K, Yadav AK, Gupta P, Rathore AS, Nayak B, Venugopal SK. Humic acid inhibits HBV‐induced autophagosome formation and induces apoptosis in HBV‐transfected Hep G2 cells. Sci Rep. 2016; 6.
dc.identifier.citedreferenceStasi C, Silvestri C, Voller F. Emerging Trends in Epidemiology of Hepatitis B Virus Infection. J Clin Translat Hepatol. 2017; 5 ( 3 ): 272 ‐ 276.
dc.identifier.citedreferenceZhou L, Zhang W, Sun Y, Jia L. Protein neddylation and its alterations in human cancers for targeted therapy. Cell Signal. 2018; 44: 92 ‐ 102.
dc.identifier.citedreferenceSoucy TA, Smith PG, Milhollen MA, et al. An inhibitor of NEDD8‐activating enzyme as a new approach to treat cancer. Nature. 2009; 458 ( 7239 ): 732 ‐ U67.
dc.identifier.citedreferenceZhao Y, Morgan MA, Sun Y. Targeting neddylation pathways to inactivate Cullin‐RING ligases for anti‐cancer therapy. Antioxid Redox Signal. 2014; 21 ( 17 ): 2383 ‐ 400.
dc.identifier.citedreferenceDuan H, Wang Y, Aviram M, et al. SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol Cell Biol. 1999; 19: 3145 ‐ 55.
dc.identifier.citedreferenceKamura T, Koepp DM, Conrad MN, et al. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science. 1999; 284: 657 ‐ 61.
dc.identifier.citedreferenceOhta T, Michel JJ, Schottelius AJ, Xiong Y. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell. 1999; 3: 535 ‐ 41.
dc.identifier.citedreferenceSwaroop M, Wang Y, Miller P, et al. Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: Chip profiling implicates its role in cell cycle regulation. Oncogene. 2000; 19: 2855 ‐ 66.
dc.identifier.citedreferenceSun Y, Tan M, Duan H, Swaroop M. SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. Antioxid Redox Signal. 2001; 3 ( 4 ): 635 ‐ 50.
dc.identifier.citedreferenceZhao Y, Sun Y. Cullin‐RING ligases as attractive anti‐cancer targets. Curr Pharm Des. 2013; 19 ( 18 ): 3215 ‐ 25.
dc.identifier.citedreferenceSwords RT, Erba HP, DeAngelo DJ, et al. Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015; 169 ( 4 ): 534 ‐ 43.
dc.identifier.citedreferencePevonedistat With Azacitidine Versus Azacitidine Alone in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia(Phase 2). National Cancer Institute (NCI) NCT03745352 NCT03745352 (PHII‐169).
dc.identifier.citedreferenceA Randomized Phase II Trial of MLN4924 (Pevonedistat) With Azacitidine Versus Azacitidine in Adult Relapsed or Refractory Acute Myeloid Leukemia(Phase 2). National Cancer Institute (NCI) NCT03745352. (NCT03745352):PHII‐169.
dc.identifier.citedreferenceLe‐Trilling VTK, Megger DA, Katschinski B, et al. Broad and potent antiviral activity of the NAE inhibitor MLN4924. Sci Rep. 2016; 6: 19977.
dc.identifier.citedreferenceStanley DJ, Bartholomeeusen K, Crosby DC, et al. Inhibition of a NEDD8 cascade restores restriction of HIV by APOBEC3G. PLoS Pathog. 2012; 8 ( 12 ): e1003085.
dc.identifier.citedreferenceHofmann H, Norton TD, Schultz ML, Polsky SB, Sunseri N, Landau NR. Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1‐mediated restriction of HIV‐1. J Virol. 2013; 87 ( 21 ): 11741 ‐ 50.
dc.identifier.citedreferenceTokarev A, Stoneham C, Lewinski MK, et al. Pharmacologic inhibition of Nedd8 activation enzyme exposes CD4‐induced epitopes within Env on Cells Expressing HIV‐1. J Virol. 2015; 90 ( 5 ): 2486 ‐ 502.
dc.identifier.citedreferenceYan Y, Huang F, Yuan T, Sun B, Yang R. HIV‐1 Vpr increases HCV replication through VprBP in cell culture. Virus Res. 2016; 223: 153 ‐ 60.
dc.identifier.citedreferenceNekorchuk MD, Sharifi HJ, Furuya AK, Jellinger R, de Noronha CM. HIV relies on neddylation for ubiquitin ligase‐mediated functions. Retrovirology. 2013; 10: 138.
dc.identifier.citedreferenceDePaula‐Silva AB, Cassiday PA, Chumley J, et al. Determinants for degradation of SAMHD1, Mus81 and induction of G2 arrest in HIV‐1 Vpr and SIVagm Vpr. Virology. 2015; 477: 10 ‐ 7.
dc.identifier.citedreferenceRamirez PW, DePaula‐Silva AB, Szaniawski M, Barker E, Bosque A, Planelles V. HIV‐1 Vpu utilizes both cullin‐RING ligase (CRL) dependent and independent mechanisms to downmodulate host proteins. Retrovirology. 2015; 12: 65.
dc.identifier.citedreferenceSun H, Yao W, Wang K, Qian Y, Chen H, Jung YS. Inhibition of neddylation pathway represses influenza virus replication and pro‐inflammatory responses. Virology. 2018; 514: 230 ‐ 9.
dc.identifier.citedreferenceDecorsière A, Mueller H, van Breugel PC, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature. 2016; 531 ( 7594 ): 386 ‐ 9.
dc.working.doi10.7302/162en
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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