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

The epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGF beta-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 I kappa B kinase (IKK) subunit IKK alpha is necessary for the silencing of E-cadherin in a Panc1 cell model of TGF beta-SMAD-mediated EMT, independently of NF kappa B. IKK alpha regulates canonical TGF beta-SMAD signaling by interacting with SMAD3 and controlling SMAD complex formation on DNA. Furthermore, we demonstrate that the TGF beta-IKK alpha-SMAD signaling pathway induces transcription of the genes encoding SNAIL and SLUG. In addition, we demonstrate that IKK alpha also modulates canonical TGF beta-SMAD signaling in human MDA-MB231 breast cancer cells, arguing for a more general impact of IKK alpha on the control of TGF beta-SMAD signaling. Taken together, these findings indicate that IKK alpha contributes to the tumor-promoting function of the TGF beta-SMAD signaling pathway in particular cancers.