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J. Biol. Chem., Vol. 280, Issue 6, 4182-4187, February 11, 2005

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Epigenetic Silencing of the Human Nucleotide Excision Repair Gene, hHR23B, in Interleukin-6-responsive Multiple Myeloma KAS-6/1 Cells^*

Benjamin Peng, David R. Hodge, Suneetha Betsy Thomas, James M. Cherry**, David J. Munroe¶, Celine Pompeia, Weihua Xiao, and William L. Farrar||

From the Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, NCI-Frederick, National Institutes of Health, Intramural Research Support Program, Science Applications International Corporation, and Laboratories of ^¶Molecular Technology and ^**Gene Expression, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

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.

Received for publication, November 8, 2004 , and in revised form, November 17, 2004.

^* This work was supported by the federal funds of the NCI, National Institutes of Health, under contract N01-CO-5600 and the Department of Health and Human Services, by contract with SAIC. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Laboratory of Molecular Immunoregulation, NCI-Frederick Cancer Research and Development Center, 1050 Boyles St., Bldg. 560, Rm. 31-68, Frederick, MD 21702. Tel.: 301-846-1503; Fax: 301-846-7042; E-mail: farrar{at}mail.ncifcrf.gov.

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