EIF1AX Nucleolar Condensates Enhance Susceptibilities for the Management of Endometrial Cancer.

Endometrial cancer harboring TP53 aberrations presents a significant therapeutic challenge due to the lack of druggable targets. A promising strategy involves inducing senescence in cancer cells followed by targeted elimination using senolytic agents. The preliminary findings indicated that the aberrant subcellular localization of EIF1AX in endometrial cancer is significantly correlated with a poor prognosis. In this study, a compound library is employed to screen for therapeutic agents that induce the nuclear localization of EIF1AX in endometrial cancer cells, followed by a CRISPR library screen to identify senolytic compounds. The results demonstrated that the combination of 2,5-MeC and dacinostat effectively inhibited tumor growth. Mechanistically, co-immunoprecipitation mass spectrometry and cleavage under targets and tagmentation sequencing analyses demonstrated that 2,5-MeC acts as a potent inducer of EIF1AX nucleolar translocation. This translocation promoted senescence by recruiting DDX21 to form nucleolar aggregates, which suppressed rDNA transcription. Additionally, RNA sequencing and antibody array analyses revealed that the synthetic lethality of 2,5-MeC and dacinostat is mediated through the activation of the JNK/MAPK signaling pathway. Collectively, these findings highlight a novel therapeutic strategy for TP53-aberrant endometrial cancer.