N-methyl-D-aspartate receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer.
Promoter hypermethylation accompanied by gene silencing is a common feature of human cancers. We identified previously several new tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of reexpression on microarray analysis. In this study, we modified the selection of candidates from our previous microarray data by excluding genes that showed basal expression in cancer cell lines. With the new method, we found novel methylated genes with 90% accuracy. Among these 33 novel methylated genes that we identified in esophageal squamous cell carcinoma (ESCC) cell lines, N-methyl-D-aspartate receptor type 2B (NMDAR2B) was of particular interest. NMDAR2B was methylated in 95% of primary human ESCC tissue specimens and 12 ESCC cell lines by sequence analysis. NMDAR2B expression was silenced in all 12 ESCC cell lines and was reactivated by the demethylating agent 5-aza-2'-deoxycytidine. Moreover, reintroduction of the gene was accompanied by marked Ca(2+)-independent apoptosis in ESCC cell lines, suggesting that NMDAR2B can suppress tumor growth. Thus, NMDAR2B promoter methylation is common in ESCC, abrogating gene transcription and leading to cellular resistance to apoptosis.
Department of Otolaryngology, Head and Neck Cancer Research Division, Institute of Cell Engineering, Johns Hopkins University School of Medicine, 818 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.
Myoung Sook
MS
Kim
Keishi
K
Yamashita
Jin Hyen
JH
Baek
Hannah Lui
HL
Park
Andre Lopes
AL
Carvalho
Motonobu
M
Osada
Mohammad Obaidul
MO
Hoque
Sunil
S
Upadhyay
Masaki
M
Mori
Chulso
C
Moon
David
D
Sidransky
D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism
C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate