title: Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma.
abstract: Ras-association domain family of proteins (RASSF) is characterized by the Ras-association (RA) domain at the C-terminal. Frequent inactivation of RASSF1A gene in human cancers suggests that other members of the family may also play an important role in tumorigenesis. By in silico gene searches, the number of RASSF family members is increasing. Two new members of RASSF family, RASSF4/AD037 and NORE1, were recently identified. While the status of RASSF4/AD037 is poorly understood, methylation of NORE1A was reported to be common in human cancers. In this study, we aimed to investigate the expression and methylation status of RASSF4/AD037 and NORE1 in nasopharyngeal carcinoma (NPC) in which RASSF1A is frequently inactivated by promoter hypermethylation. Our results showed that expression of RASSF4/AD037 was lost in 12.5% (1/8) of NPC cell lines/xenografts. Bisulfite sequencing analysis revealed dense methylation in the promoter region of RASSF4/AD037 in the cell line. Restoration of RASSF4/AD037 mRNA was observed by treatment with a demethylating agent. Moreover, methylation of primary NPC was found in 5% (1/20) of the samples examined. For NORE1A, partial methylation was detected in 37.5% (3/8) of NPC cell lines/xenografts while expression of NORE1A was found in all NPC cell lines/xenografts. No aberrant methylation of NORE1A was observed in 20 primary tumors. In summary, epigenetic inactivation of RASSF4/AD037 and NORE1A is rare in NPC, suggesting that these two RASSF family members may not be critical targets for gene inactivation during the tumorigenesis of NPC.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, The Sir Y.K. Pao Center for Cancer, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. snchow@cuhk.edu.hk
authors.forename: Lillian Shuk-Nga
authors.initials: LS
authors.lastname: Chow
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwong
authors.forename: Albert Yue-Hang
authors.initials: AY
authors.lastname: Wong
authors.forename: Dolly P
authors.initials: DP
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; C495500:RASSF4 protein, human; C454042:RASSF5 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D020559:Monomeric GTP-Binding Proteins; D001374:Azacitidine