Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA
Chronic hepatitis B virus (HBV) infection continues to be a global health concern because current treatments such as interferon-α and nucleos(t)ide analogs cannot fully eliminate the virus due to persistence of covalently closed circular DNA (cccDNA) and integrated HBV DNA. Earlier research suggests...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1537929/full |
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| author | Jumi Kim Jumi Kim Jiseon Ha Jiseon Ha Chanho Song Chanho Song Muhammad Azhar Sajjad Muhammad Azhar Sajjad Fadia Kalsoom Hyeonjoong Kwon Hyeonjoong Kwon Jaewoo Park Sun Park Sun Park Kyongmin Kim Kyongmin Kim |
| author_facet | Jumi Kim Jumi Kim Jiseon Ha Jiseon Ha Chanho Song Chanho Song Muhammad Azhar Sajjad Muhammad Azhar Sajjad Fadia Kalsoom Hyeonjoong Kwon Hyeonjoong Kwon Jaewoo Park Sun Park Sun Park Kyongmin Kim Kyongmin Kim |
| author_sort | Jumi Kim |
| collection | DOAJ |
| description | Chronic hepatitis B virus (HBV) infection continues to be a global health concern because current treatments such as interferon-α and nucleos(t)ide analogs cannot fully eliminate the virus due to persistence of covalently closed circular DNA (cccDNA) and integrated HBV DNA. Earlier research suggests that AGK2, a selective SIRT2 inhibitor, suppresses HBV replication by modifying key signaling pathways. This study aimed to further explore the anti-HBV effects of AKG2, particularly its effects on the epigenetic landscape of cccDNA. HBV-transfected and -infected cells were used to assess the impact of AGK2 on viral replication. Changes in SIRT2 expression and α-tubulin acetylation (SDS-PAGE-immunoblotting), core particle formation (native agarose gel electrophoresis and immunoblotting), HBV RNA (northern blotting) and DNA (Southern blotting) synthesis, and cccDNA levels (Southern blotting) were measured. Chromatin immunoprecipitation assays were performed to examine deposition of transcriptionally repressive epigenetic markers on cccDNA. AGK2 reduced expression of SIRT2, increased acetylated α-tubulin levels, and reduced synthesis of HBV RNA and DNA. Importantly, AGK2 also reduced cccDNA levels and increased deposition of repressive histone markers H4K20me1, H3K27me3, and H3K9me3 on cccDNA, mediated by histone lysine methyltransferases such as PR-Set7, EZH2, SETDB1, and SUV39H1. Additionally, there was a reduction in recruitment of RNA polymerase II and acetylated H3 to cccDNA, indicating that AGK2 enhances transcriptional repression. AGK2 suppresses HBV replication through direct antiviral actions, and by epigenetic modulation of cccDNA, indicating that using AGK2 to target SIRT2 and associated epigenetic regulators shows promise as a functional cure for chronic hepatitis B. |
| format | Article |
| id | doaj-art-241e2517875c4f1694bb2175e8d3bc73 |
| institution | DOAJ |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-241e2517875c4f1694bb2175e8d3bc732025-08-20T03:05:13ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-04-011510.3389/fcimb.2025.15379291537929Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNAJumi Kim0Jumi Kim1Jiseon Ha2Jiseon Ha3Chanho Song4Chanho Song5Muhammad Azhar Sajjad6Muhammad Azhar Sajjad7Fadia Kalsoom8Hyeonjoong Kwon9Hyeonjoong Kwon10Jaewoo Park11Sun Park12Sun Park13Kyongmin Kim14Kyongmin Kim15Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaDepartment of Microbiology, Ajou University School of Medicine, Suwon, Republic of KoreaDepartment of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of KoreaChronic hepatitis B virus (HBV) infection continues to be a global health concern because current treatments such as interferon-α and nucleos(t)ide analogs cannot fully eliminate the virus due to persistence of covalently closed circular DNA (cccDNA) and integrated HBV DNA. Earlier research suggests that AGK2, a selective SIRT2 inhibitor, suppresses HBV replication by modifying key signaling pathways. This study aimed to further explore the anti-HBV effects of AKG2, particularly its effects on the epigenetic landscape of cccDNA. HBV-transfected and -infected cells were used to assess the impact of AGK2 on viral replication. Changes in SIRT2 expression and α-tubulin acetylation (SDS-PAGE-immunoblotting), core particle formation (native agarose gel electrophoresis and immunoblotting), HBV RNA (northern blotting) and DNA (Southern blotting) synthesis, and cccDNA levels (Southern blotting) were measured. Chromatin immunoprecipitation assays were performed to examine deposition of transcriptionally repressive epigenetic markers on cccDNA. AGK2 reduced expression of SIRT2, increased acetylated α-tubulin levels, and reduced synthesis of HBV RNA and DNA. Importantly, AGK2 also reduced cccDNA levels and increased deposition of repressive histone markers H4K20me1, H3K27me3, and H3K9me3 on cccDNA, mediated by histone lysine methyltransferases such as PR-Set7, EZH2, SETDB1, and SUV39H1. Additionally, there was a reduction in recruitment of RNA polymerase II and acetylated H3 to cccDNA, indicating that AGK2 enhances transcriptional repression. AGK2 suppresses HBV replication through direct antiviral actions, and by epigenetic modulation of cccDNA, indicating that using AGK2 to target SIRT2 and associated epigenetic regulators shows promise as a functional cure for chronic hepatitis B.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1537929/fullhepatitis B viruscovalently closed circular DNASIRT2 inhibitor AGK2repressive histone lysine methyltransferasesepigenetic suppression |
| spellingShingle | Jumi Kim Jumi Kim Jiseon Ha Jiseon Ha Chanho Song Chanho Song Muhammad Azhar Sajjad Muhammad Azhar Sajjad Fadia Kalsoom Hyeonjoong Kwon Hyeonjoong Kwon Jaewoo Park Sun Park Sun Park Kyongmin Kim Kyongmin Kim Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA Frontiers in Cellular and Infection Microbiology hepatitis B virus covalently closed circular DNA SIRT2 inhibitor AGK2 repressive histone lysine methyltransferases epigenetic suppression |
| title | Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA |
| title_full | Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA |
| title_fullStr | Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA |
| title_full_unstemmed | Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA |
| title_short | Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA |
| title_sort | sirtuin 2 inhibitor agk2 exerts antiviral effects by inducing epigenetic suppression of hepatitis b virus covalently closed circular dna through recruitment of repressive histone lysine methyltransferases and reduction of cccdna |
| topic | hepatitis B virus covalently closed circular DNA SIRT2 inhibitor AGK2 repressive histone lysine methyltransferases epigenetic suppression |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1537929/full |
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