Frequent concomitant epigenetic silencing of the stress-responsive tumor suppressor gene CADM1, and its interacting partner DAL-1 in nasal NK/T-cell lymphoma.
Nasal NK/T-cell lymphoma (NL) is a rare but clinically important entity of lymphoma. Its preferential incidence in Orientals but not Caucasians suggests possible genetic predisposition. 11q deletion is common in NL, indicating certain tumor suppressor genes (TSGs) at this locus involved in its pathogenesis. We investigated the expression and methylation of an 11q23.2 TSG, CADM1 (or TSLC1), and its partner DAL-1 (or EPB41L3) in NL. Methylation and silencing of CADM1 were detected in 2 NL and 4 of 8 (50%) of non-Hodgkin lymphoma (NHL) cell lines, but not in normal NK cells and normal PBMC. Absence of CADM1 protein was also detected in NL cell lines. 5-aza-2'-deoxycytidine (Aza) demethylation or genetic knockout of both DNMT1 and 3B genes restored CADM1 and DAL-1 expression. CADM1 methylation was further detected in 36 of 45 (80%) of NL tumors. Concomitantly, DAL-1 was epigenetically inactivated in NL cell lines and virtually all the tumors with methylated CADM1. A significant correlation between the methylation of both genes was found (p < 0.0001). Homozygous deletion of CADM1 was detected in only 3 of 18 (17%) of tumors. The stress-response of CADM1 was abolished when its promoter becomes methylated. Our results demonstrate a frequent, predominant epigenetic silencing of CADM1 and DAL-1 in NL, which likely play a synergic role in NL pathogenesis.
Fu
Li
L
Johns Hopkins Singapore, Singapore.
Gao
Zifen
Z
Zhang
Xiaohua
X
Tsang
Ying Hung
YH
Goh
Hwee Koon
HK
Geng
Hua
H
Shimizu
Norio
N
Tsuchiyama
Junjiro
J
Srivastava
Gopesh
G
Tao
Qian
Q
D015153:Blotting, Western; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D054391:Lymphoma, Extranodal NK-T-Cell / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008840:Microfilament Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; C116887:EPB41L3 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025521:Tumor Suppressor Proteins