IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

Abstract

The epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway is an inductor of EMT in many tumor types. One hallmark of EMT is downregulation of the adherens junction protein E-cadherin, a process mediated by transcription factors such as the zinc fingers SNAIL and SLUG. Here, we report that the catalytic IκB kinase (IKK) subunit IKKα is necessary for the silencing of E-cadherin in a Panc1 cell model of TGFβ–SMAD-mediated EMT, independently of NFκB. IKKα regulates canonical TGFβ–SMAD signaling by interacting with SMAD3 and controlling SMAD complex formation on DNA. Furthermore, we demonstrate that the TGFβ–IKKα–SMAD signaling pathway induces transcription of the genes encoding SNAIL and SLUG. In addition, we demonstrate that IKKα also modulates canonical TGFβ–SMAD signaling in human MDA-MB231 breast cancer cells, arguing for a more general impact of IKKα on the control of TGFβ–SMAD signaling. Taken together, these findings indicate that IKKα contributes to the tumor-promoting function of the TGFβ–SMAD signaling pathway in particular cancers.