Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Abstract

Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)–FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2–FOXE1–Snail signalling axis may thus represent a promising therapeutic strategy. AF6, an essential protein for the organization of cell-to-cell junctions and development, is aberrantly expressed in several tumors but its role in pancreatic cancer is not clear. Here the authors show that in pancreatic cancer, loss of AF6 expression leads to induction of the EMT transcription factor Snail.