title: Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects Hodgkin lymphoma cells from apoptosis.
abstract: The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor-negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis.
authors: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
authors: Paul G
authors: PG
authors: Murray
authors: Yichao
authors: Y
authors: Fan
authors: Gillian
authors: G
authors: Davies
authors: Jianming
authors: J
authors: Ying
authors: Hua
authors: H
authors: Geng
authors: Ka Man
authors: KM
authors: Ng
authors: Hongyu
authors: H
authors: Li
authors: Zifen
authors: Z
authors: Gao
authors: Wenbin
authors: W
authors: Wei
authors: Shikha
authors: S
authors: Bose
authors: Jennifer
authors: J
authors: Anderton
authors: Georgia
authors: G
authors: Kapatai
authors: Gary
authors: G
authors: Reynolds
authors: Akihiko
authors: A
authors: Ito
authors: Teresa
authors: T
authors: Marafioti
authors: Ciaran Bj
authors: CB
authors: Woodman
authors: Richard
authors: R
authors: Ambinder
authors: Qian
authors: Q
authors: Tao
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D011401:Promoter Regions, Genetic; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D025521:Tumor Suppressor Proteins