Sox7 Is an independent checkpoint for beta-catenin function in prostate and colon epithelial cells.
The presence of somatic beta-catenin mutations in some prostate cancers implies that aberrant WNT signaling is involved in the cancer development. Although beta-catenin stability is regulated by a multicomponent destruction complex, mutational alterations of beta-catenin or other components of the destruction complexes are rare in prostate tumors. Therefore, beta-catenin may be regulated by another protein in the prostate. In fact, recent linkage and somatic deletion analyses in prostate cancers reveal a 1.4-Mb candidate tumor suppressor locus on 8p23.1, which includes the Sox7 gene. Here we show that Sox7 protein expression was indeed down-regulated in 47% (15 of 32) of prostate adenocarcinomas. In addition, Sox7 mRNA was down-regulated in 60% of snap-frozen tumors. This down-regulation was found to be due to tumor-specific promoter hypermethylation, which was present in 48% (10 of 21) of primary prostate tumors and 44% (11 of 25) of prostate cancer cell lines/xenografts. We discovered that Sox7 protein physically interacts with beta-catenin and suppresses beta-catenin-mediated transcription by depleting active beta-catenin. Furthermore, in HCT116 colorectal cancer cell lines with Sox7 inactivation, ectopic Sox7 expression suppressed cell proliferation and inhibited transcription that was activated by an endogenous mutant beta-catenin. Although nearly all colorectal cancers contain mutations in beta-catenin or adenomatous polyposis coli/axin, epigenetic silencing of Sox7 was still observed. These data suggest that Sox7 is a tumor suppressor that functions as an independent checkpoint for beta-catenin transcriptional activity. Inactivation of Sox7 could promote the development of a majority of colorectal tumors and approximately half of prostate tumors.
Guo
Lizheng
L
Department of Hematology and Oncology, The Winship Cancer Institute, Atlanta VA Medical Center, Atlanta, George, USA.
Zhong
Diansheng
D
Lau
Stephen
S
Liu
Xiuju
X
Dong
Xue-Yuan
XY
Sun
Xiaodong
X
Yang
Vincent W
VW
Vertino
Paula M
PM
Moreno
Carlos S
CS
Varma
Vijay
V
Dong
Jin-Tang
JT
Zhou
Wei
W
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D022981:Allelic Imbalance; D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055760:SOXF Transcription Factors; D017386:Sequence Homology, Amino Acid; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000502:physiology*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; C484456:SOX7 protein, human; D055760:SOXF Transcription Factors; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases