SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer
16.09.2014
Rönsch K, Jägle S, Rose K, Seidl M, Baumgartner F, Freihen V, Yousaf A, Metzger E, Lassmann S, Schüle R, Zeiser R, Michoel T, Hecht A.
Mol Oncol. 2015;9(2):335-54.
EPHB3 is a cellular guidance factor in the intestinal epithelium and an important tumor suppressor in colorectal cancer (CRC). EPHB3 expression is frequently downregulated at the adenoma-carcinoma transition by mechanisms that are incompletely understood. Our study identifies SNAIL1 - an inducer of epithelial-mesenchymal-transition (EMT) - as transcriptional repressor of EPHB3. SNAIL1 competitively displaces activator proteins and engages corepressor complexes containing HDACs and the histone demethylase LSD1 to collapse active chromatin structure at a critical transcriptional enhancer element. Our findings identify EPHB3 as a novel target of the SNAIL1 and indicate that inactivation of EPHB3 signaling is an important aspect to trigger an EMT process.
