NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx.
Metastasis-associated protein 1 (MTA1), a master chromatin modifier, has been shown to regulate cancer progression and is widely upregulated in human cancer, including hepatitis B virus-associated hepatocellular carcinomas (HCCs). Here we provide evidence that hepatitis B virus transactivator protein HBx stimulates the expression of MTA1 but not of MTA2 or MTA3. The underlying mechanism of HBx stimulation of MTA1 involves HBx targeting of transcription factor nuclear factor (NF)-kappaB and the recruitment of HBx/p65 complex to the NF-kappaB consensus motif on the relaxed MTA1 gene chromatin. We also discovered that MTA1 depletion in HBx-expressing cells severely impairs the ability of HBx to stimulate NF-kappaB signaling and the expression of target proinflammatory molecules. Furthermore, the presence of HBx in HBx-infected HCCs correlated well with increased MTA1 and NF-kappaB-p65. Collectively, these findings revealed a previously unrecognized integral role of MTA1 in HBx stimulation of NF-kappaB signaling and consequently, the expression of NF-kappaB targets gene products with functions in inflammation and tumorigenesis.
Bui-Nguyen
T M
TM
Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA.
Pakala
S B
SB
Sirigiri
R D
RD
Xia
W
W
Hung
M-C
MC
Sarin
S K
SK
Kumar
V
V
Slagle
B L
BL
Kumar
R
R
D006528:Carcinoma, Hepatocellular / Q000821:virology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006515:Hepatitis B virus / Q000737:chemistry*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000502:physiology; D015534:Trans-Activators / Q000494:pharmacology*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
D017362:Cyclic AMP Response Element-Binding Protein; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D051996:Transcription Factor RelA; D054334:Viral Regulatory and Accessory Proteins; C115163:CREB1 protein, human; C057628:hepatitis B virus X protein; C120917:MTA2 protein, human