Premium
Frequent concomitant epigenetic silencing of the stress‐responsive tumor suppressor gene CADM1 , and its interacting partner DAL‐1 in nasal NK/T‐cell lymphoma
Author(s) -
Fu Li,
Gao Zifen,
Zhang Xiaohua,
Tsang Ying Hung,
Goh Hwee Koon,
Geng Hua,
Shimizu Norio,
Tsuchiyama Junjiro,
Srivastava Gopesh,
Tao Qian
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24123
Subject(s) - epigenetics , gene silencing , biology , methylation , cancer research , tumor suppressor gene , lymphoma , dna methylation , microbiology and biotechnology , pathogenesis , gene , carcinogenesis , gene expression , immunology , genetics
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. © 2008 Wiley‐Liss, Inc.