title: Epigenetic silencing of cellular retinol-binding proteins in nasopharyngeal carcinoma.
abstract: Aberrant retinoid signaling in human cancers is extending from the nucleus to the cytoplasm. Recently, we have demonstrated frequent epigenetic inactivation of a retinoic acid receptor (RAR), RARbeta2, in nasopharyngeal carcinoma (NPC). To further explore targets contributing to aberrant retinoid signaling in NPC, the expression of cellular retinol-binding proteins (CRBPs), cellular retinoic acid-binding proteins (CRABPs), RARs, and retinoid X receptors (RXRs) was examined. Apart from RARbeta2, transcriptional silencing of two CRBPs, CRBPI and CRBPIV, was observed in NPC cell lines and xenografts. Hypermethylation of CRBPI and CRBPIV CpG islands was found to be closely correlated with the loss of expression. Treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, resulted in reexpression of CRBP1 and CRBPIV gene expression in NPC cell lines. Both CRBPI and CRBPIV hypermethylations were also observed in 43/48 (87.8%) and 26/48 (54.2%) primary NPC tumors, respectively. Here, we reported for the first time that CRBPIV was transcriptionally inactivated by promoter hypermethylation in human cancer. Simultaneous methylation of CRBPI, CRBPIV, and RARbeta2 was commonly found in NPC primary tumors. Our findings implied that epigenetic disruption of the CRBPs, CRBPI and CRBPIV, is important in NPC tumorigenesis and may contribute to the loss of retinoic acid responsiveness in cancer.
authors.affiliation: Department of Anatomical and Cellular Pathology, Hong Kong, SAR, China.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwong
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Lillian Shuk-Nga
authors.initials: LS
authors.lastname: Chow
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Kwong-Wai
authors.initials: KW
authors.lastname: Choy
authors.forename: Franky Leung
authors.initials: FL
authors.lastname: Chan
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.forename: Dolly P
authors.initials: DP
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009305:Nasopharynx / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012176:Retinoids / Q000494:pharmacology*; D012177:Retinol-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D012176:Retinoids; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D000077209:Decitabine; D001374:Azacitidine
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