MDM4/MDM2 double knockdown in CRC cells revives p53 activity and has synergistic effect with anti-tumor drugs, including cytotoxic 5-FU [120] and MEK inhibitor trametinib [121], but another study found that impaired activity of MDM2 confers irradiation resistance to CRC cells [122], suggesting that regulating E3 enzyme activity is a double-edged sword and deserves further investigations before the translation into clinical trials. Here, MDM2 is linked to colorectal carcinoma.