GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-A (TNFa) mediated IKKb activation-impaired GLI1 binding with theE3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.
ASJC Scopus subject areas
- Cell Biology