Jiandong Sun

EIF1AX Nucleolar Condensates Enhance Susceptibilities for the Management of Endometrial Cancer

Abstract 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.

XPO1‐Mediated EIF1AX Cytoplasmic Relocation Promotes Tumor Migration and Invasion in Endometrial Carcinoma

Dysregulation of eukaryotic translation initiation factor 1A, X‐linked (EIF1AX), has been implicated in the pathogenesis of some cancers. However, the role of EIF1AX in endometrial carcinoma (EC) remains unknown. We investigated the EIF1AX expression in EC patients and assessed its tumorigenesis‐associated function and nucleocytoplasmic transport mechanism in vitro and in vivo. The results indicated that the cytoplasmic EIF1AX expression showed a gradual increase when going from endometrium normal tissue, simple endometrial hyperplasia, complex endometrial hyperplasia, and endometrial atypical hyperplasia to EC, while vice versa for the nuclear EIF1AX expression. In addition, the cytoplasmic EIF1AX expression was positively correlated with histologic type, high International Federation of Gynecology and Obstetrics (FIGO) grade, advanced FIGO stage, deeper infiltration, high Ki67 index, and shorter recurrence‐free survival in EC patients. In vitro, short hairpin RNA‐mediated EIF1AX depletion or SV40NLS‐mediated EIF1AX import into the nucleus in multiple human EC cells potently suppressed cell migration and invasion, epithelial‐mesenchymal transition, and lung metastasis. Moreover, exportin 1 induced the transport of EIF1AX from the nucleus to the cytoplasm that could be inhibited by leptomycin B treatment or the mutation in the EIF1AX location sequence. These results demonstrate that cytoplasmic EIF1AX may play a key role in the incidence and promotion of EC, and thus, targeting EIF1AX or its nucleocytoplasmic transport process may offer an effective new therapeutic approach to EC.