Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer.
FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation-mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression.
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
Yan
Y
Song
M Kay
MK
Washington
Howard C
HC
Crawford
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004847:Epithelial Cells / Q000473:pathology; D020868:Gene Silencing; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000096:biosynthesis* / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D015820:Cadherins; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D034741:RNA, Small Interfering; D051542:Hepatocyte Nuclear Factor 3-beta