Parvovirus nonstructural proteins induce an epigenetic modification through histone acetylation in host genes and revert tumor malignancy to benignancy.
Several malignant tumor cells become apoptotic and revert to the benign phenotype upon parvovirus infection. Recently, we demonstrated that the rat parvovirus RPV/UT also induces apoptosis in the rat thymic lymphoma cell line C58(NT)D. However, a minority of cells that escaped apoptosis showed properties different from the parental cells, such as resistance to apoptosis, enhanced cell adherence, and suppressed tumorigenicity. The present study was performed to determine the molecular mechanism of parvovirus-induced phenotypic modification, including oncosuppression. We demonstrated that the nonstructural (NS) proteins of RPV/UT induced apoptosis in C58(NT)D cells and suppressed tumor growth in vivo. Interestingly, NS proteins induced the expression of ciliary neurotrophic factor receptor alpha, which is up-regulated in revertant cell clones, and enhanced histone acetylation of its gene. These results indicate that parvoviral NS regulate host gene expression through histone acetylation, suggesting a possible mechanism of oncosuppression.
Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Hiroyoshi
H
Iseki
Rie
R
Shimizukawa
Fumihiro
F
Sugiyama
Satoshi
S
Kunita
Atsushi
A
Iwama
Masafumi
M
Onodera
Hiromitsu
H
Nakauchi
Ken-ichi
K
Yagami
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D009687:Nuclear Proteins / Q000502:physiology; D017992:Parvovirus / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000502:physiology*
D006657:Histones; D009687:Nuclear Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D015534:Trans-Activators; D017361:Viral Nonstructural Proteins; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C494365:Crebbp protein, rat