EYA4 promotes cellular senescence by enhancing P21 transcription through interaction with SIX2

During the aging process, the expression levels of numerous genes undergo significant changes, some of which in turn regulate the progression of aging. In this study, we identified the expression of EYA4 is upregulated during aging and demonstrated its critical role in modulating cellular senescence. Knockdown of EYA4 significantly delays both replicative and stress-induced cellular senescence. Mechanistic investigations showed that EYA4 interacts with the transcription factor SIX2 to promote the expression of p21, a key molecule in the senescence-signaling pathway, which accelerates cellular senescence. Interestingly, EYA4 possesses both transcriptional activation and phosphatase activities, yet experiments using phosphatase-deficient mutants revealed that its ability to enhance p21 expression is independent of its phosphatase activity. Further analysis demonstrated that the EYA4-SIX2-mediated regulation of p21 expression is p53-dependent, as the absence of p53 abolished this regulatory effect. In conclusion, our findings uncover a novel role of the EYA4-SIX2 complex in promoting cellular senescence through the transcriptional activation of p21. Targeting EYA4 may represent a promising strategy for delaying the aging process.