title: The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma.
abstract: Loss of heterozygosity at 3p21 is common in various cancers including nasopharyngeal carcinoma (NPC). BLU is one of the candidate tumor suppressor genes (TSGs) in this region. Ectopic expression of BLU results in the inhibition of colony formation of cancer cells, suggesting that BLU is a tumor suppressor. We have identified a functional BLU promoter and found that it can be activated by environmental stresses such as heat shock, and is regulated by E2F. The promoter and first exon are located within a CpG island. BLU is highly expressed in testis and normal upper respiratory tract tissues including nasopharynx. However, in all seven NPC cell lines examined, BLU expression was downregulated and inversely correlated with promoter hypermethylation. Biallelic epigenetic inactivation of BLU was also observed in three cell lines. Hypermethylation was further detected in 19/29 (66%) of primary NPC tumors, but not in normal nasopharyngeal tissues. Treatment of NPC cell lines with 5-aza-2'-deoxycytidine activated BLU expression along with promoter demethylation. Although hypermethylation of RASSF1A, another TSG located immediately downstream of BLU, was detected in 20/27 (74%) of NPC tumors, no correlation between the hypermethylation of these two TSGs was observed (P=0.6334). In addition to methylation, homozygous deletion of BLU was found in 7/29 (24%) of tumors. Therefore, BLU is a stress-responsive gene, being disrupted in 83% (24/29) of NPC tumors by either epigenetic or genetic mechanisms. Our data are consistent with the interpretation that BLU is a TSG for NPC.
authors.affiliation: Cancer Epigenetics/Tumor Virology Laboratory, Division of Johns Hopkins in Singapore, Singapore.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Qiu
authors.forename: Luke K S
authors.initials: LK
authors.lastname: Tan
authors.forename: Kwok Seng
authors.initials: KS
authors.lastname: Loh
authors.forename: Chai Yen
authors.initials: CY
authors.lastname: Lim
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Sen-Tien
authors.initials: ST
authors.lastname: Tsai
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D000483:Alleles; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D002893:Chromosomes, Human, Pair 3; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013312:Stress, Physiological / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine