IκB kinase-ε-mediated phosphorylation triggers IRF-1 degradation in breast cancer cells

Anna Lisa Remoli, Marco Sgarbanti, Edvige Perrotti, Marta Acchioni, Roberto Orsatti, Chiara Acchioni, Angela Battistini, Robert Clarke, Giulia Marsili

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Interferon Regulatory Factors (IRFs) are key regulators of immunity, cell survival and apoptosis. IRF transcriptional activity and subcellular localization are tightly regulated by posttranscriptional modifications including phosphorylation. The IκB kinase family member IKK-ε is essential in regulating antiviral innate immunity mediated by IRFs but is now also recognized as an oncoprotein amplified and overexpressed in breast cancer cell lines and patient-derived tumors. In the present study, we report that the tumor suppressor IRF-1 is a specific target of IKK-ε in breast cancer cells. IKK-ε-mediated phosphorylation of IRF-1 dramatically decreases IRF-1 protein stability, accelerating IRF-1 degradation and quenching IRF-1 transcriptional activity. Chemical inhibition of IKK-ε activity, fully restores IRF-1 levels and function and positively correlates with inhibition of cell growth and proliferation of breast cancer cells. By using a breast cancer cell line stably expressing a dominant negative version of IRF-1 we were able to demonstrate that IKK-ε preferentially exerts its oncogenic potential in breast cancer through the regulation of IRF-1 and point to the IKK-ε-mediated phosphorylation of IRF-1 as a therapeutic target to overcome IKK-ε-mediated tumorigenesis.

Original languageEnglish (US)
Pages (from-to)459-469
Number of pages11
JournalNeoplasia (United States)
Issue number10
StatePublished - Oct 2020

Bibliographical note

Funding Information:
This work was supported by ISS intramural research grant (A.B. and M.S.)

Publisher Copyright:
© 2020


  • IKK-ε
  • IRF-1
  • K48 polyubiquitination
  • breast cancer
  • phosphorylation
  • protein stability


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