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

## TL;DR

This study identifies a new treatment strategy for endometrial cancer by using compounds that induce senescence and then eliminate cancer cells.

## Contribution

The study introduces a novel therapeutic approach using 2,5-MeC and dacinostat to target TP53-aberrant endometrial cancer.

## Key findings

- The combination of 2,5-MeC and dacinostat effectively inhibited tumor growth in endometrial cancer.
- 2,5-MeC induces EIF1AX nucleolar translocation, promoting senescence by recruiting DDX21 and suppressing rDNA transcription.
- The synthetic lethality of 2,5-MeC and dacinostat is mediated through the JNK/MAPK signaling pathway.

## 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.

This schematic illustrates the mechanism of a senolytic strategy in endometrial cancer. EIF1AX facilitates the incorporation of DDX21 into nucleolar condensates, an event that suppresses rDNA transcription and induces cellular senescence. The compound 2,5‐MeC exploits this pathway by promoting EIF1AX nucleolar translocation and condensate formation. Subsequently, the combination of dacinostat and 2,5‐MeC eliminates these senescent cells by inducing apoptosis.