摘要
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.
基金
This study was supported by the National Natural Science Foundation of China(81871653,82072286 and 82073251)
Natural Science Foundation of Chongqing(cstc2020jcyj-msx mX0159,cstc2018jcyjAX0254 and cstc2019jcyj-msxmX0587)
Chongqing Medical Science Project(2018MSXM065)
Technology Research Project of Chongqing Municipal Education Commission(KJQN201900449
KJZD-M202000401)
Scientific Research Innovation Project for Postgraduates in Chongqing(CYS19193 and CYB19168).
