Investigation of novel avenues for cancer treatment and mechanisms of post-stress recovery

Integration of ChIP-seq, RNA-seq, and functional validation studies revealed that KDM4A orchestrates comprehensive cellular adaptation to stress through four distinct regulatory mechanisms targeting specific gene programs. KDM4A coordinates both immediate stress adaptation and preparation for recovery by simultaneously activating stress response programs while suppressing energy-intensive processes.<br><br>Notably, depletion of KDM4A significantly enhanced the sensitivity of CRC cells to PIis and 5-FU in a p53-dependent manner, with pronounced cytotoxic effects observed in wild-type but not p53-null cells.

Immunofluorescence analysis demonstrated that PIis disrupt the spatial relationship between KDM4A and RNA Polymerase I within the nucleolus, suggesting a mechanistic basis for this enhanced sensitivity.<br><br>Together, these findings establish PIis as promising therapeutic agents for CRC, particularly in combination with 5-FU, and identify KDM4A as a key coordinator of stress response and drug sensitivity. This research advances our understanding of epigenetic regulation during stress and suggests new approaches for cancer treatment that exploit the convergence of nucleolar stress and DNA damage response pathways, potentially addressing challenges of chemotherapy resistance in colorectal cancer.