Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing.
Aberrant promoter hypermethylation of tumor suppressor genes is proposed to be a common feature of primary cancer cells. We recently developed a pharmacological unmasking microarray approach to screen unknown tumor suppressor gene candidates epigenetically silenced in human cancers. In this study, we applied this method to identify such genes in head and neck squamous cell carcinoma (HNSCC). We identified 12 novel methylated genes in HNSCC cell lines, including PGP9.5, cyclin A1, G0S2, bone-morphogenetic protein 2A, MT1G, and neuromedin U, which showed frequent promoter hypermethylation in primary HNSCC (60%, 45%, 35%, 25%, 25%, and 20%, respectively). Moreover, we discovered that cyclin A1 methylation was inversely related to p53 mutational status in primary tumors (P = 0.015), and forced expression of cyclin A1 resulted in robust induction of wild-type p53 in HNSCC cell lines. Pharmacological unmasking followed by microarray analysis is a powerful tool to identify key methylated tumor suppressor genes and relevant pathways.
Tokumaru
Yutaka
Y
Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
Yamashita
Keishi
K
Osada
Motonobu
M
Nomoto
Shuji
S
Sun
Dong-Il
DI
Xiao
Yan
Y
Hoque
Mohammad Obaidul
MO
Westra
William H
WH
Califano
Joseph A
JA
Sidransky
David
D
D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000235:genetics*; D056750:Cyclin A1; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C503745:CCNA1 protein, human; D019925:Cyclin A; D056750:Cyclin A1; D016159:Tumor Suppressor Protein p53