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.