Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer.
Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. 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.
Suzuki
Hiromu
H
Division of Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, Maryland 21231, USA.
Watkins
D Neil
DN
Jair
Kam-Wing
KW
Schuebel
Kornel E
KE
Markowitz
Sanford D
SD
Chen
Wei Dong
WD
Pretlow
Theresa P
TP
Yang
Bin
B
Akiyama
Yoshimitsu
Y
Van Engeland
Manon
M
Toyota
Minoru
M
Tokino
Takashi
T
Hinoda
Yuji
Y
Imai
Kohzoh
K
Herman
James G
JG
Baylin
Stephen B
SB
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins
D006023:Glycoproteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins