ABSTRACT
Although the transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-κB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-κB pathway suppresses senescence in murine dermal fibroblasts. IκB kinase β (IKKβ)-depleted dermal fibroblasts showed ineffective NF-κB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated β-galactosidase (SA-β-gal) staining and p16INK4a mRNA levels. Conversely, the expression of constitutively active IKKβ (IKKβ-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of κB (IκB), which inhibits NF-κB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKβ-CA on senescence is largely mediated by NF-κB. We also found that IKKβ-CA expression suppressed the derepression of INK4/Arf genes and counteracted the senescence-associated loss of Ezh2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2). Moreover, pharmacological inhibition of Ezh2 abolished IKKβ-CA-induced senescence bypass. We propose that NF-κB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression.
Acknowledgements
We are grateful to Prof. Michael Karin (University of California, San Diego, CA) for generous permission to use IKKβ flox mice.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
MH and KSH designed and performed the study; TK, KO and NA supervised the study; MH, KSH and NA analyzed and interpreted the data; MH and KSH wrote the manuscript
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2325802