Wnt activation and alternative promoter repression of LEF1 in colon cancer.
Alternative promoters within the LEF1 locus produce polypeptides of opposing biological activities. Promoter 1 produces full-length LEF-1 protein, which recruits beta-catenin to Wnt target genes. Promoter 2 produces a truncated form that cannot interact with beta-catenin and instead suppresses Wnt regulation of target genes. Here we show that promoter 1 is aberrantly activated in colon cancers because it is a direct target of the Wnt pathway. T-cell factor (TCF)-beta-catenin complexes bind to Wnt response elements in exon 1 and dynamically regulate chromatin acetylation and promoter 1 activity. Promoter 2 is delimited to the intron 2/exon 3 boundary and, like promoter 1, is also directly regulated by TCF-beta-catenin complexes. Promoter 2 is nevertheless silent in colon cancer because an upstream repressor selectively targets the basal promoter leading to destabilized TCF-beta-catenin binding. We conclude that the biological outcome of aberrant LEF1 activation in colon cancer is directed by differential promoter activation and repression.
Li
Tony W-H
TW
Department of Microbiology and Molecular Genetics, Rm. B240, Medical Sciences I, University of California, Irvine, Irvine, CA 92697-4025, USA. mlwaterm@uci.edu
Ting
Ju-Hui T
JH
Yokoyama
Noriko N
NN
Bernstein
Alla
A
van de Wetering
Marc
M
Waterman
Marian L
ML
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019169:Jurkat Cells; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D002843:Chromatin; D004273:DNA, Neoplasm; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin