WNT7a induces E-cadherin in lung cancer cells.
E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/beta-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently downregulated in lung cancer, and that loss of E-cadherin or beta-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a beta-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3 beta inhibitor, led to E-cadherin induction in an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free beta-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.
Ohira
Tatsuo
T
Division of Medical Oncology, Department of Biometrics/Preventive Medicine, University of Colorado Health Sciences and Cancer Centers, 4200 East 9th Avenue, Denver, CO 80262, USA.
Gemmill
Robert M
RM
Ferguson
Kevin
K
Kusy
Sophie
S
Roche
Joëlle
J
Brambilla
Elisabeth
E
Zeng
Chan
C
Baron
Anna
A
Bemis
Lynne
L
Erickson
Paul
P
Wilder
Elizabeth
E
Rustgi
Anil
A
Kitajewski
Jan
J
Gabrielson
Edward
E
Bremnes
Roy
R
Franklin
Wilbur
W
Drabkin
Harry A
HA
D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006655:Histone Deacetylases / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000494:pharmacology / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C092778:WNT7A protein, human; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases