Palmitoylation of Smad2 assists TGFβ-Smad signaling to promote breast cancer metastasis

Although the role of palmitic acid (PA) as a membrane component in promoting cancer invasion and migration has been explored, it remains unclear whether and how PA enhances breast cancer metastasis via palmitoylation modification. Here, we observed that PA promotes epithelial-mesenchymal transition (EMT), invasion, and migration in breast cancer cells, which could be antagonized by the palmitoyl-transferase inhibitor 2-bromopalmitate (2-BP) through regulating TGFβ-Smad pathway. Specifically, we screened and identified that Smad2 undergoes ZDHHC7-mediated palmitoylation, which stabilizes Smad2 protein, enhances Smad2/Smad3 interaction, and promotes their binding to DNA elements following TGFβ stimulation, thereby promoting EMT. Consequently, ZDHHC7 enhanced breast cancer cell migration, and its depletion effectively suppressed breast cancer lung metastasis. Based on these findings, we generated cell-penetrating peptides to block Smad2 palmitoylation, resulting in disrupting its interaction with Smad3, and in turn attenuate breast cancer EMT, invasion, and migration in cells and in orthotopic mouse models. In summary, our study reveals a novel mechanism by which PA promotes breast cancer metastasis through ZDHHC7-mediated palmitoylation of Smad2, and proposes a therapeutic strategy to inhibit breast cancer lung metastasis by using a specific peptide targeting this modification.