title: Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6-responsive multiple myeloma KAS-6/1 cells.
abstract: During tumorigenesis, selective proliferative advantage in certain cell subsets is associated with accumulation of multiple genetic alterations. For instance, multiple myeloma is characterized by frequent karyotypic instability at the earliest stage, progressing to extreme genetic abnormalities as the disease progresses. These successive genetic alterations can be attributed, in part, to defects in DNA repair pathways, perhaps based on epigenetic gene silencing of proteins involved in DNA damage repair. Here we report epigenetic hypermethylation of the hHR23B gene, a key component of the nucleotide excision repair in response to DNA damage, in interleukin-6 (IL-6)-responsive myeloma KAS-6/1 cells. This hypermethylation was significantly abated by Zebularine, a potent demethylating agent, with a consequent increase in the hHR23B mRNA level. Subsequent removal of this drug and supplementation with IL-6 in the culture medium re-established DNA hypermethylation of the hHR23B gene and silencing of mRNA expression levels. The inclination of DNA to be remethylated, at least within the hHR23B gene promoter region, reflects an epigenetic driving force by the cytogenetic/tumorigenic status of KAS-6/1 myeloma. The IL-6 response of KAS-6/1 myeloma also raises a question of whether the proneoplastic growth factor, such as IL-6, supports the epigenetic silencing of important DNA repair genes via promoter hypermethylation during the development of multiple myeloma.
authors.affiliation: Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peng
authors.forename: David R
authors.initials: DR
authors.lastname: Hodge
authors.forename: Suneetha Betsy
authors.initials: SB
authors.lastname: Thomas
authors.forename: James M
authors.initials: JM
authors.lastname: Cherry
authors.forename: David J
authors.initials: DJ
authors.lastname: Munroe
authors.forename: Celine
authors.initials: C
authors.lastname: Pompeia
authors.forename: Weihua
authors.initials: W
authors.lastname: Xiao
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D003470:Culture Media / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D045643:DNA Repair Enzymes; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007621:Karyotyping; D007700:Kinetics; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
chemical_list: D003470:Culture Media; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011741:Pyrimidine Nucleosides; C513287:RAD23B protein, human; D012333:RNA, Messenger; D013447:Sulfites; C086985:RAD23A protein, human; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D003596:Cytosine; D004247:DNA; D045643:DNA Repair Enzymes