In conclusion, our results present in this study demonstrate that ACER2 is upregulated in p53-proficient cancer cell lines but not p53-defieint cell lines in response to DNA damage and that ACER2 upregulation mediates PCD in response to a high degree of DNA damage by accumulating SPH, a bioactive lipid that in turn induces cellular ROS production. Here, ACER2 is linked to cancer.