Investigating the role of IKKε (epsilon) in cancer-associated NF-κB activity Public Deposited

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  • March 21, 2019
Creator
  • Adli, Mezher
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • Nuclear Factor κB (NF-κB) has been studied extensively as an inducible transcriptional regulator of the immune and inflammatory responses. NF-κB activation downstream of LPS or cytokine stimulation is controlled by the IκB kinase complex which contains IKKα and IKKβ and NEMO. Significantly, the constitutive activity of NF-κB has been implicated as an important aspect of many cancer cells but mechanisms associated with this activity are poorly understood. An inducible kinase, IKK-i / IKKε, related to the catalytic forms of the IκB kinase, has been studied as an anti-viral, innate immune regulator through its ability to control the activity of the transcription factors IRF-3 and IRF-7. Here, we demonstrate that IKK-i / IKKε is expressed in a number of cancer cells and is involved in regulating NF-κB activity through its ability to control basal/constitutive, but not cytokine induced, p65/RelA phosphorylation at ser536, a modification proposed to contribute to the transactivation function of NF-κB. Knockdown of IKK-i / IKKε or expression of a S536A mutant form of p65 suppresses HeLa cell proliferation. The data indicate a role for IKK-i / IKKε in controlling proliferation of certain cancer cells through regulation of constitutive NF-κB activity. Moreover, microarray analysis of gene expression profiles in cancer cells with RNAi mediated IKKε knock-down demonstrated a number of genes that are highly regulated by IKKε. Among these genes, we were particularly interested in the Bcl-3 oncogene. After the observation that Bcl-3 gene expression is significantly reduced in microarray data following IKKε knock-down, we further confirmed and validated the microarray data by showing that overexpression of IKKε significantly upregulates Bcl-3 gene expression and that IKKε knock down downregulates it. Moreover, our data suggest that Bcl-3 gene expression is defective in IKKε knock-out MEF cells both at the protein level and at the message level. Promoter studies indicate that IKKε regulates Bcl-3 gene expression through NF-κB. We have also observed a significant correlation between IKKε expression and Bcl-3 expression in HCC tumors compared to adjacent tissue. My hypothesis is that IKKε regulation in cancer promotes oncogenic potential partly through the induced regulation of Bcl-3.
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  • Baldwin, Albert
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