Nature Genetics
36, 417 - 422 (2004)
Published online: 14 March 2004; | doi:10.1038/ng1330
Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancerHiromu Suzuki1, 2, D Neil Watkins1, Kam-Wing Jair1, Kornel E Schuebel1, Sanford D Markowitz3, 4, Wei Dong Chen4, Theresa P Pretlow5, Bin Yang1, Yoshimitsu Akiyama1, Manon van Engeland6, Minoru Toyota2, 7, 8, Takashi Tokino7, Yuji Hinoda9, Kohzoh Imai2, James G Herman1
& Stephen B Baylin11
Division of Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, Maryland 21231, USA. 2
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan. 3
Howard Hughes Medical Institute, Cleveland, Ohio 44106, USA. 4
Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA. 5
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. 6
Department of Pathology, University of Maastricht, 6200 MD Maastricht, the Netherlands. 7
Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan. 8
PRESTO, JST, Kawaguchi, Japan. 9
Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Yamaguchi, Japan.
Correspondence should be addressed to Stephen B Baylin sbaylin@jhmi.eduAberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers1. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding  -catenin)1,
2,
3 or AXIN2 (encoding axin-2, also known as conductin)4. These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free -catenin in the nucleus1,
2,
3. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer5. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development6,
7,
8,
9,
10. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.
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