Abstract
We previously demonstrated that the NF-κB inhibitor IκBα binds the chromatin together with PRC2 to regulate a subset of developmental- and stem cell-related genes. This alternative function has been elusive in both physiological and disease conditions because of the predominant role of IκBα as a negative regulator of NF-κB.
We here uniquely characterize specific residues of IκBα that allow the generation of separation-of-function (SOF) mutants that are defective for either NF-κB-related (SOFΔNF-κB) or chromatin-related (SOFΔH2A,H4) activities. Expression of IκBα SOFΔNF-κB, but not SOFΔH2A/H4, is sufficient to negatively regulate a specific stemness program in intestinal cells, thus rescuing the differentiation blockage imposed by IκBα deficiency. In contrast, full IκBα activity is required for regulating clonogenic/tumor-initiating activity of colorectal cancer cells.
Our data indicate that SOF mutants represent an exclusive tool for studying IκBα functions in physiology and disease, and identified IκBα as a robust prognosis biomarker for human cancer.
Competing Interest Statement
Anna Bigas, Laura Sole and Lluis Espinosa have a submitted patent related with SOF IκBα mutants
Footnotes
↵& All should be considered first authors
