The Ets family transcription factor EHF suppresses senescence-associated inflammatory responses
Cellular senescence is a tumor-suppressive program characterized by irreversible growth arrest; however, senescent cells can also promote inflammation and alter the tumor microenvironment through the senescence-associated secretory phenotype (SASP). Although SASP induction is regulated by pathways such as p38/NF-{kappa}B/I{kappa}B{zeta}, the mechanisms that restrain excessive or persistent SASP remain largely unknown. Here, we investigated the role of the Ets family transcription factor EHF in SASP regulation during cellular senescence. In IMR-90 human fibroblasts undergoing oncogene-induced senescence, EHF expression was upregulated after the onset of canonical senescence phenotypes. EHF knockdown did not substantially affect senescence establishment but increased SASP-related gene expression. Conversely, overexpression of full-length EHF suppressed SASP-related gene induction during senescence, whereas an ETS-domain-deficient EHF mutant failed to do so, suggesting that this EHF-mediated SASP suppression requires its DNA-binding domain. Furthermore, knockdown of NFKBIZ, which encodes I{kappa}B{zeta} and is induced downstream of NF-{kappa}B signaling, reduced EHF expression during senescence; however, NFKBIZ overexpression increased EHF and SASP-related gene expression. These results link EHF induction to the p38/NF-{kappa}B/I{kappa}B{zeta} inflammatory axis and support a model in which the inflammatory pathway that induces SASP also engages EHF as a negative regulator of SASP. Finally, conditioned medium from senescent cells promoted HCT116 cancer cell migration, and this activity showed a further increase after EHF knockdown. These findings suggest that EHF suppresses senescence-associated inflammatory responses and may function as a senomorphic effector that attenuates SASP-related inflammation without substantially affecting senescence establishment.