IKKα Activation of NOTCH Links Tumorigenesis via FOXA2 Suppression

Abstract

SUMMARY Pro-inflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/ S111, thereby suppressing FOXA2 transactivation activity, leading to decreased NUMB expression and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

“…Of every cell type, 10 7 cells of extracted nuclear proteins from each condition were denatured by boiling at 95°C for 10 min. 1D gel electrophoresis was as de scribed previously (Liu et al, 2012) and performed with 10% SDS PAGE. After the gel was stained using VisPRO 5 min protein stain kit (VP01 500; Visual Protein), every lane was cut off into 10 equal sections, followed by re duction with  mercaptoethanol (1% vol/vol) in 25 mM ammonium bicar bonate at room temperature in the dark for 20 min, and alkylation with 5% vol/vol 4 vinylpyridine in 25 mM ammonium bicarbonate for 20 min.…”

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

“…The Notch signaling pathway is known to promote various types of human tumors, such as hepatocellular carcinoma (HCC) and breast cancer [4][5][6]. The Notch pathway comprises a family of transmembrane receptors and ligands, modifiers and transcription factors [7].…”

“…The Notch pathway comprises a family of transmembrane receptors and ligands, modifiers and transcription factors [7]. Following activation of the Notch pathway, the Notch intracellular domain (NIC) translocates to the nucleus to activate transcription of target genes [4]. Aberrant activation of the Notch pathway leads to various diseases including cancer [4,7].…”

Crosstalk between the Notch signaling pathway and non‑coding RNAs in gastrointestinal cancers (Review)

“…Conserved helix-loop-helix ubiquitous kinase (IKKa) is a direct target of miR-148a, which binds to the 3'UTR site of IKKa mRNA. It has been reported that IKKα may mediate Notch signaling activation through regulation of NUMB, Endocytic Adaptor Protein (NUMB), as NUMB may inhibit Notch signaling in HCC (59)(60)(61). The silencing of IKKa may induce hepatocytic differentiation, a similar effect to the upregulation of miR-148, whilst the overexpression of Notch2 may reverse this phenomenon (58).…”