Programmed cell death 5 (PDCD5) regulates cell death and suppresses tumor progression. Since the stability and nuclear translocation of PDCD5 are regulated by TP53-dependent cell death stimuli, knowledge of the regulatory mechanism of PDCD5 function is required to better understand the TP53-signaling pathway. We identified Jumonji domain-containing protein 4 (JMJD4) to be a PDCD5-interacting protein using liquid chromatography- mass spectrometry (LC-MS). Interestingly, JMJD4 upregulates cell proliferation and chemo-resistance under genotoxic stress conditions by colony-formation assay and decreases TP53-related apoptotic genes (BAX, PUMA) by suppressing protein levels of PDCD5. Additionally, using the Cancer Genome Atlas and the Gene Expression Omnibus database to confirm the clinical correlation between JMJD4 and cancer patients, we verified that JMJD4 is associated with a poor prognosis in colon cancer and lung cancer patients. Therefore, this study demonstrates that JMJD4 directly interacts with PDCD5, regulates cancer cell death negatively, and could be a potential therapeutic target for cancer development. [BMB Reports 2025
58(2): 64-69].