STAT3 stabilizes IKKα protein through direct interaction in transformed and cancerous human breast epithelial cells

Young Il Hahn, Soma Saeidi, Su Jung Kim, Se Young Park, Na Young Song, Jie Zheng, Do Hee Kim, Han Byoel Lee, Wonshik Han, Dong Young Noh, Hye Kyung Na, Young Joon Surh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-κB pathway as well as the classical one. The α subunit of the inhibitor of the κB kinase (IKK) complex, IKKα, is involved in both classical and non-classical activation of NF-κB. Although the cross-talk between STAT3 and NF-κB has been suggested in several studies, the interplay between STAT3 and the regulators of NF-κB including IKKα has not been fully clarified yet. In this study, we observed overexpression and co-localization of IKKα and STAT3 in human breast cancer tissues as well as in H-Ras transformed human breast epithelial (H-Ras MCF-10A) and breast cancer (MDA-MB-231) cells. By utilizing small interfering RNA (siRNA) technology, we were able to demonstrate that STAT3 up-regulated IKKα, but not IKKβ or IKKγ, in these cells. This was attributable to direct binding to and subsequent stabilization of IKKα protein by blocking the ubiquitin-proteasome system. Notably, we identified the lysine 44 residue of IKKα as a putative binding site for STAT3. Moreover, siRNA knockdown of IKKα attenuated viability, anchorage-independent growth and migratory capabilities of H-Ras MCF-10A cells. Taken together, these findings propose a novel mechanism responsible for NF-κB activation by STAT3 through stabilization of IKKα, which contributes to breast cancer promotion and progression. Thus, breaking the STAT3-IKKα alliance can be an alternative therapeutic strategy for the treatment of breast cancer.

Original languageEnglish
Article number82
Pages (from-to)1-15
Number of pages15
JournalCancers
Volume13
Issue number1
DOIs
StatePublished - Dec 2021

Keywords

  • Breast cancer
  • H-Ras MCF-10A cells
  • IKKα
  • Non-canonical NF-κB pathway
  • STAT3

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