WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer.
OBJECTIVE
Aberrant activation of the Wnt/beta-catenin signaling pathway is associated with multiple tumors including colorectal cancer (CRC). WNT5A is a member of the nontransforming Wnt protein family, whose role in tumorigenesis is still ambiguous. We investigated its epigenetic alteration in CRCs.


METHODS
We examined its expression and methylation in normal colon, CRC cell lines, and tumors. We also evaluated its tumor-suppressive function and its modulation to Wnt signaling in CRC cells.


RESULTS
WNT5A is silenced in most CRC cell lines due to promoter methylation, but is expressed in most normal tissues including the colon, and is unmethylated in normal colon epithelial cells. WNT5A expression could be reactivated by pharmacologic or genetic demethylation, indicating that methylation directly mediates its silencing. WNT5A methylation was frequently detected in CRC tumors (14 of 29, 48%), but only occasionally in paired normal colon tissues (2 of 15, 13%; P = 0.025). Ectopic expression of WNT5A, but not its nonfunctional short-isoform with the WNT domain deleted, in silenced CRC cells resulted in substantial inhibition of tumor cell clonogenicity, which is associated with down-regulated intracellular beta-catenin protein level and concomitant decrease in beta-catenin activity.


CONCLUSIONS
WNT5A is frequently inactivated in CRC by tumor-specific methylation, and thus, is a potential biomarker. WNT5A could act as a tumor suppressor for CRC by antagonizing the Wnt/beta-catenin signaling.
Ying
Jianming
J
Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Department of Clinical Oncology, Sir Y.K. Pao Center for Cancer, Hong Kong Cancer Institute, Hong Kong, China.
Li
Hongyu
H
Yu
Jun
J
Ng
Ka Man
KM
Poon
Fan Fong
FF
Wong
Sze Chuen Cesar
SC
Chan
Anthony T C
AT
Sung
Joseph J Y
JJ
Tao
Qian
Q
D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin