JDP2 is directly regulated by ATF4 and modulates TRAIL sensitivity by suppressing the ATF4–DR5 axis

Jun dimerization protein 2 (JDP2) is a bZip‐type transcription factor, which acts as a repressor or activator of several cellular processes, including cell differentiation and chromatin remodeling. Previously, we found that a stress‐responsive transcription factor, known as activating transcription factor 4 (ATF4), enhances JDP2 gene expression in human astrocytoma U373MG and cervical cancer HeLa cells; however, the role of JDP2 in the ATF4‐mediated stress response remained unclear. Here, we reported that siRNA‐mediated JDP2 knockdown enhances the expression of several ATF4 target genes, including ASNS, and death receptors 4 and 5 (DR4 and DR5) in HeLa cells. In addition, the results of a transient reporter assay indicate that JDP2 overexpression represses ER stress‐mediated DR5 promoter activation suggesting that JDP2 negatively regulates ATF4‐mediated gene expression. Curiously, knockdown of JDP2 increases the sensitivity of cells to TNF‐related apoptosis‐inducing ligand (TRAIL), which induces apoptosis in cancer cells through DR4 and DR5. These results indicate that JDP2 functions as a negative feedback regulator of the ATF4 pathway and contributes to TRAIL resistance in cancer cells.