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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.
- Source :
-
Oncogene [Oncogene] 2004 Jun 10; Vol. 23 (27), pp. 4793-806. - Publication Year :
- 2004
-
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.
- Subjects :
- Alleles
Animals
Azacitidine pharmacology
Base Sequence
Carcinoma pathology
Cell Line
Cell Line, Tumor
Cell Transformation, Viral
CpG Islands
DNA Methylation
Decitabine
Enzyme Inhibitors pharmacology
Gene Deletion
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Humans
Mice
Mice, Nude
Molecular Sequence Data
Nasopharyngeal Neoplasms pathology
Promoter Regions, Genetic
Protein Binding
Azacitidine analogs & derivatives
Carcinoma genetics
Chromosomes, Human, Pair 3
Epigenesis, Genetic
Nasopharyngeal Neoplasms genetics
Stress, Physiological genetics
Tumor Suppressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 23
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 15122337
- Full Text :
- https://doi.org/10.1038/sj.onc.1207632