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

Abstract

IkB proteins are the primary inhibitors of NF-kB. Here, we demonstrate that sumoylated and phosphorylated IkBa accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IkBa modulates Polycomb recruitment and imparts their competence to be activated by TNFa. Mutations in the Drosophila IkBa gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-kB. Oncogenic transformation of keratinocytes results in cytoplasmic IkBa translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IkBa was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation.