Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects Hodgkin lymphoma cells from apoptosis.
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.
Murray
Paul G
PG
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
Fan
Yichao
Y
Davies
Gillian
G
Ying
Jianming
J
Geng
Hua
H
Ng
Ka Man
KM
Li
Hongyu
H
Gao
Zifen
Z
Wei
Wenbin
W
Bose
Shikha
S
Anderton
Jennifer
J
Kapatai
Georgia
G
Reynolds
Gary
G
Ito
Akihiko
A
Marafioti
Teresa
T
Woodman
Ciaran Bj
CB
Ambinder
Richard
R
Tao
Qian
Q
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
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D025521:Tumor Suppressor Proteins