Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma.
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.
Carvalho
André Lopes
AL
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287-0910, USA.
Chuang
Alice
A
Jiang
Wei-Wen
WW
Lee
Juna
J
Begum
Shahnaz
S
Poeta
Luana
L
Zhao
Ming
M
Jerónimo
Carmen
C
Henrique
Rui
R
Nayak
Chetan S
CS
Park
Hannah L
HL
Brait
Mariana R O
MR
Liu
Chunyan
C
Zhou
Shaoyu
S
Koch
Wayne
W
Fazio
Vito Michele
VM
Ratovitski
Edward
E
Trink
Barry
B
Westra
William
W
Sidransky
David
D
Moon
Chul-so
CS
Califano
Joseph A
JA
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D000075389:DCC Receptor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016163:Genes, DCC; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology; D000075388:Netrin-1; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000075389:DCC Receptor; C501909:DCC protein, human; D004273:DNA, Neoplasm; C000617351:NTN1 protein, human; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1