Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression

Chen, Yu Fang; Chong, Chin Liew; Wu, Yi; Wang, Yi Ling; Tsai, Kuen Nan; Kuo, Tzer Min; Hong, Ming Hsiang; Hu, Cheng; Chen, Mong Liang; Chou, Yi-Chun; Chang, Chung-Ming

doi:10.1371/journal.pone.0131743

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…The precise mechanisms of HBV reactivation upon administration of different agents remain largely unknown, but has been linked either to the impairment of immune responses (TNF-α inhibitors, B-cell depleting agents, chemokine and integrin inhibitors, kinase inhibitors, proteasome inhibitors) or activation of transcription of HBV covalently closed circular DNA (cccDNA) (histone deacetylase inhibitors) [5]. Several lines of evidence indicate that HBV reactivation may be related to oxidative stress, DNA damage/DNA damage response and interconnected alterations in the intracellular signaling and cell cycle progression in the infected cells [9,10,11,12,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

Kostyusheva

Brezgin

Bayurova

et al. 2019

Viruses

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Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

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Section: Introductionmentioning

confidence: 99%

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

Kostyusheva

Brezgin

Bayurova

et al. 2019

Viruses

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“…HDACi-induced G1/S phase arrest might contribute to de novo HBV replication before cells enter into mitosis, and regulation of some transcriptional factors which are involved in cell growth and differentiation, such as E2F transcription factor 5, CCAAT/enhancer-binding protein α (C/EBPα), hepatocyte nuclear factor 4 alpha, etc. 39 Increased p21 has been shown to recruit C/EBPα to the HBV promoter after doxorubicin treatment; 40 thus, FK228/SAHA-induced elevated p21/p27 expression might stimulate HBV replication by increasing the recruitment of C/EBPα or other transcriptional factors to HBV promoters. In addition, HDACi treatment has been reported to induce the depletion of uracil DNA glycosylase, which can counteract APOBEC3-induced hypermutations.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Romidepsin and Vorinostat Promote Hepatitis B Virus Replication by Inducing Cell Cycle Arrest

Yang

Chen

et al. 2021

Journal of Clinical and Translational Hepatology

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Background and Aims: Chronic hepatitis B virus (HBV) infection is a global public health challenge. HBV reactivation usually occurs in cancer patients after receiving cytotoxic chemotherapy or immunosuppressive therapies. Romidepsin (FK228) and vorinostat (SAHA) are histone deacetylase inhibitors (HDACi) approved by the Food and Drug Administration as novel antitumor agents. The aim of this study was to explore the effects and mechanisms of HDACi treatment on HBV replication. Methods: To assess these effects, human hepatoma cell lines were cultured and cell viability after FK228 or SAHA treatment was measured by the CCK-8 cell counting kit-8 assay. Then, HBV DNA and RNA were quantified by real-time PCR and Southern blotting. Furthermore, analysis by western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and flow cytometry was performed. Results: FK228/SAHA treatment significantly promoted HBV replication and biosynthesis in both HBV-replicating cells and HBV-transgenic mouse model. Flow cytometry assay indicated that FK228/SAHA enhanced HBV replication by inducing cell cycle arrest through modulating the expression of cell cycle regulatory proteins. In addition, simultaneous inhibition of HDAC1/2 by FK228 promoted HBV replication more effectively than the broad spectrum HDAC inhibitor SAHA. Conclusions: Overall, our results demonstrate that cell cycle blockage plays an important role in FK228/SAHAenhanced HBV replication, thus providing a potential avenue for rational use of HDACi in patients with chronic hepatitis B.

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“…Previous studies reported that doxorubicin and other chemotherapeutic medications enhanced HBV replication in HBV-expressing hepatoma cells 18 . Doxorubicin induced P21(Waf1/Cip1) expression and enhanced the binding of CCAAT/enhancer-binding protein α to the HBV core promoter, thereby contributing to enhanced HBV replication 28 Recently, Mouler Rechtman M et al . reported that anticancer cytotoxic agents induce PGC-1α upregulation and coactivate HBV transcription 29 .…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress

Pan

Zhu

et al. 2018

Sci Rep

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Chronic hepatitis B infection remains a serious public health issue worldwide. Hepatitis B virus (HBV) reactivation is commonly reported in patients receiving anticancer therapy, immunosuppressive therapy, or organ and tissue transplantation. However, the precise mechanisms underlying chemotherapeutic agent-related HBV reactivation remain unclear. Here, we report that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) plays a central role in cisplatin-induced HBV transcription and replication. First, cisplatin treatment upregulated the expression levels of PGC-1α and hepatocyte nuclear factor 4 alpha (HNF-4α) in both HBV-replicating cells and an HBV-transgenic mouse model. PGC-1α coactivates with HNF-4α, which interacts with a core promoter and enhancer II region of HBV genome, thereby promoting HBV production. In contrast, knockdown of PGC-1α and HNF-4α by RNA interference in hepatoma cells reversed HBV activation in response to cisplatin. Additionally, PGC-1α upregulation depended on cisplatin-mediated endoplasmic reticulum (ER) stress. We further observed that the recruitment of cyclic AMP-responsive element-binding protein plays a crucial role for PGC-1α transcriptional activation in cisplatin-treated cells. Finally, pharmacologic inhibition of ER stress impaired PGC-1α upregulation and HBV production induced by cisplatin treatment. These findings demonstrate novel molecular mechanisms indicating that ER stress-PGC1α signaling pathway plays a critical role in cisplatin-evoked HBV reactivation.

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Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression

Cited by 13 publications

References 37 publications

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

Histone Deacetylase Inhibitors Romidepsin and Vorinostat Promote Hepatitis B Virus Replication by Inducing Cell Cycle Arrest

Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress

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