Role Of ATF3in Colon Cancer Cells Apoptosis By HDAC Inhibitors Through ER Stress

Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy.However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fullyelucidated. Death receptor5(DR5) is a transmembrane receptor containing death domain thattriggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducingligand) or agonistic anti-DR5monoclonal antibody, and the combination of TRAIL/agonisticanti-DR5monoclonal antibody and agents that increase the expression of DR5is expected asa novel anticancer therapeutic strategy. Here we report that six different HDACIs activatedendoplasmic reticulum (ER) stress sensor PERK and eIF2and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increasedexpression of DR5on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5monoclonal antibody. Stress response gene ATF3was required for efficient DR5induction byHDACIs, and DR5reporter assay showed that ATF3play crucial role for theHDACIs-induced activation of DR5gene transcription. These provide important mechanisticinsight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatmentswhen they are used in combination with other therapeutic strategies.