Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma.

Abstract

Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC(+/-)) showed a similar frequency of tumor formation compared with the wild-type mice (DCC(+/+)). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2'-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC.

• Authors: André Lopes Carvalho, Alice Chuang, Wei-Wen Jiang, Juna Lee, Shahnaz Begum, Luana Poeta, Ming Zhao, Carmen Jerónimo, Rui Henrique, Chetan S Nayak, Hannah L Park, Mariana R O Brait, Chunyan Liu, Shaoyu Zhou, Wayne Koch, Vito Michele Fazio, Edward Ratovitski, Barry Trink, William Westra, David Sidransky, Chul-so Moon, Joseph A Califano
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 19 Pg. 9401-7 (Oct 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 17018594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DCC Receptor
• DCC protein, human
• DNA, Neoplasm
• NTN1 protein, human
• Neoplasm Proteins
• Nerve Growth Factors
• Ntn1 protein, mouse
• Receptors, Cell Surface
• Tumor Suppressor Proteins
• Netrin-1

Topics

• Carcinoma, Squamous Cell (genetics, pathology)
• Cell Line, Tumor
• CpG Islands (genetics)
• DCC Receptor
• DNA Methylation
• DNA, Neoplasm (chemistry, genetics)
• Gene Expression Regulation, Neoplastic
• Genes, DCC
• Head and Neck Neoplasms (genetics, pathology)
• Humans
• Loss of Heterozygosity
• Neoplasm Proteins (biosynthesis, deficiency, genetics, physiology)
• Nerve Growth Factors (genetics, physiology)
• Netrin-1
• Promoter Regions, Genetic (genetics)
• Receptors, Cell Surface (biosynthesis, deficiency, physiology)
• Transfection
• Tumor Suppressor Proteins (biosynthesis, deficiency, genetics, physiology)