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Figure 1. Tumorigenic functions of IKKα and IKKα(p45). In CRC, IKKα phosphorylates the nuclear co-repressors N-CoR and SMRT, inducing their dissociation from chromatin. IKKα(p45) is activated by BRAF and TAK1 in the endosomal compartment, and upon activation phosphorylates histone H3 and SMRT. Inhibitors of the endosomal acidification such as chloroquine or Bafilomycin A1 would prevent IKKα(p45) phosphorylation and impair gene transcription necessary for cancer cell survival. Moreover, nuclear active IKKα contributes to chromatin release of phospho-SUMO-IκBα facilitating its cytoplasmic export. IKKα regulates gene transcription of metastasis repressor Maspin in prostate cancer cells. Under damaging conditions, IKKα(p45) is phosphorylated via BRAF/TAK1/p38-MAPK, inducing its nuclear translocation. In the nucleus, IKKα(p45) induces phosphorylation of ATM and 53BP1, which would favor the recruitment of RIF1 to 53BP1^[4]. Altogether, the activation of these factors would induce DNA repair and survival of cancer cells. Blocking BRAF activity would block IKKα(p45) activation and cancer cell survival. Arrows indicate activation/regulation/phosphorylation, dashed arrows indicate migration, and the red cross indicates inactivation. CRC: colorectal cancer; IKKα: inhibitor of kappaB kinase alpha; BRAF: serine/threonine-specific protein kinase of the RAF family; TAK1: TGFβ-Activated kinase 1; SMRT: silencing-mediator for retinoid/thyroid hormone receptors; MAPK: mitogen-activated protein kinase; ATM: ataxia telangiectasia mutated gene; NEMO: NF-κB essential modulator; PRC2: polycomb repressive complex 2; KAP1: KRAB-associated protein-1; RIF1: replication timing regulatory factor 1