A splicing variant of NME1 negatively regulates NF-κB signaling and inhibits cancer metastasis by interacting with IKKβ

Dong Joo You, Cho Rong Park, Hyun Bok Lee, Mi Jin Moon, Ju Hee Kang, Cheolju Lee, Seong Hyun Oh, Curie Ahn, Jae Young Seong, Jong-Ik Hwang

Research output: Contribution to journalArticle

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Abstract

IKKβ functions as a principal upstream activator of the canonical NF-κB pathway by phosphorylating IκB, leading to its proteasomal degradation. Because IKKβ is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKβ-interacting molecule, NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its antimetastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKKβ. Exogenous expression of NME1L resulted in a potent decrease in TNFα-stimulated NF-κB activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF-κB. NME1L down-regulates IKKβ signaling by blocking IKKβ-mediated IκB degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in a metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent antimetastatic protein and may be a useful weapon in the fight against cancers.

Original languageEnglish
Pages (from-to)17709-17720
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number25
DOIs
Publication statusPublished - 2014 Jun 20

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Neoplasm Metastasis
Degradation
Molecules
Small Interfering RNA
Assays
Neoplasms
Proteins
Chemical activation
Weapons
Down-Regulation
Lung
Research
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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A splicing variant of NME1 negatively regulates NF-κB signaling and inhibits cancer metastasis by interacting with IKKβ. / You, Dong Joo; Park, Cho Rong; Lee, Hyun Bok; Moon, Mi Jin; Kang, Ju Hee; Lee, Cheolju; Oh, Seong Hyun; Ahn, Curie; Seong, Jae Young; Hwang, Jong-Ik.

In: Journal of Biological Chemistry, Vol. 289, No. 25, 20.06.2014, p. 17709-17720.

Research output: Contribution to journalArticle

You, Dong Joo ; Park, Cho Rong ; Lee, Hyun Bok ; Moon, Mi Jin ; Kang, Ju Hee ; Lee, Cheolju ; Oh, Seong Hyun ; Ahn, Curie ; Seong, Jae Young ; Hwang, Jong-Ik. / A splicing variant of NME1 negatively regulates NF-κB signaling and inhibits cancer metastasis by interacting with IKKβ. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 25. pp. 17709-17720.
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