title: Epigenetic silencing of manganese superoxide dismutase (SOD-2) in KAS 6/1 human multiple myeloma cells increases cell proliferation.
abstract: The generation of reactive oxygen species (ROS) by mitochondrial electron transport chain (ETC) and oxidative phosphorylation activity, has been linked to modifications of multiple molecular processes, including lipid peroxidation, signaling pathway and transcription factor modulation, and oxidative damage to DNA. Oxidative damage by endogenous ROS has been associated with the etiology of various pathological states. There are numerous reports that levels of manganese superoxide dismutase enzyme (MnSOD), an antioxidant enzyme responsible for the attenuation of ROS, are lowered in cancer cells, but the reasons for this reduction are poorly defined. Epigenetic silencing of genes involved in tumor suppression and DNA repair is known to occur in a variety of malignant cell types. Here we report that in the human multiple myeloma cell line KAS 6/1, the SOD-2 gene, encoding manganese superoxide dismutase, is epigenetically silenced as a result of promoter hypermethylation. The DNA methyltransferase inhibitor Zebularine reverses SOD-2 promoter methylation, increasing gene expression and enzyme levels. Infection of KAS 6/1 cells with a recombinant adenovirus carrying the MnSOD cDNA reduced the cell proliferation rate by approximately one-half, confirming the detrimental effects of epigenetic silencing of SOD-2 expression.
authors.affiliation: Laboratory of Molecular Immunoregulation, Cytokine Molecular Mechanisms Section, Center for Cancer Research, The National Cancer Institute at Frederick, Frederick, MD 21702, USA. hodge@mail.ncifcrf.gov
authors.forename: David R
authors.initials: DR
authors.lastname: Hodge
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peng
authors.forename: Celine
authors.initials: C
authors.lastname: Pompeia
authors.forename: Suneetha
authors.initials: S
authors.lastname: Thomas
authors.forename: Edward
authors.initials: E
authors.lastname: Cho
authors.forename: Peter A
authors.initials: PA
authors.lastname: Clausen
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D013482:Superoxide Dismutase