Chromatin-Bound IκBα Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer

IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation. [Display omitted] •Sumoylated and phosphorylated IκBα binds H2A and H4 in keratinocytes•IκBα regulates keratinocyte differentiation and transformation•IκBα regulates Polycomb chromatin release and HOX expression in response to TNFα•IκBα cooperates with Polycomb in Drosophila patterning