Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors.
Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5' CpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through beta-catenin/T-cell factor-independent mechanisms.
First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan.
Hironobu
H
Sato
Hiromu
H
Suzuki
Minoru
M
Toyota
Masanori
M
Nojima
Reo
R
Maruyama
Shigeru
S
Sasaki
Hideyasu
H
Takagi
Yohei
Y
Sogabe
Yasushi
Y
Sasaki
Masashi
M
Idogawa
Tomoko
T
Sonoda
Mitsuru
M
Mori
Kohzoh
K
Imai
Takashi
T
Tokino
Yasuhisa
Y
Shinomura
D048868:Adaptor Proteins, Signal Transducing; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C501126:DKK1 protein, human; C498622:DKK2 protein, human; C498624:DKK3 protein, human; C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins