Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-KappaB pathway activation in lung cancer

Kelsie L. Thu, Larissa A. Pikor, Raj Chari, Ian M. Wilson, Calum E. MacAulay, John C. English, Ming Sound Tsao, Adi F. Gazdar, Stephen Lam, Wan L. Lam, William W. Lockwood

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37 Scopus citations

Abstract

Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) (IKK-β/IKK-2), which activates NF-κB, is a substrate of the KEAP1-CUL3-RBX1 E3-ubiquitin ligase complex, implicating this complex in NF-κB pathway regulation. We investigated complex component gene disruption as a novel genetic mechanism of NF-κB activation in non-small cell lung cancer. Methods: A total of 644 tumor- and 90 cell-line genomes were analyzed for gene dosage status of the individual complex components and IKBKB. Gene expression of these genes and NF-κB target genes were analyzed in 48 tumors. IKBKB protein levels were assessed in tumors with and without complex or IKBKB genetic disruption. Complex component knockdown was performed to assess effects of the E3-ligase complex on IKBKB and NF-κB levels, and phenotypic importance of IKBKB expression was measured by pharmacological inhibition. Results: We observed strikingly frequent genetic disruption (42%) and aberrant expression (63%) of the E3-ligase complex and IKBKB in the samples examined. Although both adenocarcinomas and squamous cell carcinomas showed complex disruption, the patterns of gene disruption differed. IKBKB levels were elevated with complex disruption, knockdown of complex components increased activated forms of IKBKB and NF-κB proteins, and IKBKB inhibition detriments cell viability, highlighting the biological significance of complex disruption. NF-κB target genes were overexpressed in samples with complex disruption, further demonstrating the effect of complex disruption on NF-κB activity. Conclusions: Gene dosage alteration is a prominent mechanism that disrupts each component of the KEAP1-CUL3-RBX1 complex and its NF-κB stimulating substrate, IKBKB. Herein, we show that, multiple component disruption of this complex represents a novel mechanism of NF-κB activation in non-small cell lung cancer.

Original languageEnglish (US)
Pages (from-to)1521-1529
Number of pages9
JournalJournal of Thoracic Oncology
Volume6
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • CUL3
  • Genetic disruption
  • IKBKB
  • KEAP1
  • NF-κB signaling
  • RBX1

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Thu, K. L., Pikor, L. A., Chari, R., Wilson, I. M., MacAulay, C. E., English, J. C., Tsao, M. S., Gazdar, A. F., Lam, S., Lam, W. L., & Lockwood, W. W. (2011). Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-KappaB pathway activation in lung cancer. Journal of Thoracic Oncology, 6(9), 1521-1529. https://doi.org/10.1097/JTO.0b013e3182289479