CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer

Worldwide, gastric cancer is one of the most fatal cancers. Epigenetic alterations in gastric cancer play important roles in silencing of tumor suppressor genes. We previously found that CXXC finger protein 4 (CXXC4) was a novel tumor suppressor in gastric cancer. In this report, we demonstrated that CXXC4 inhibited growth of gastric cancer cells as a pro-apoptotic factor. This inhibition could be reversed by the pan-caspase inhibitor called Z-VAD-FMK. However, CXXC4 with mutations in its DNA binding domain failed to induce apoptosis. Growth differentiation factor 15 (GDF15) was identified as one of potential targets responsible for CXXC4-induced apoptosis. CXXC4 activated GDF15 transcription through enhancing the interaction of transcription factor Sp1 with GDF15 promoter. In summary, the nuclear protein CXXC4 activated apoptosis in gastric cancer through up-regulating its novel potential downstream target GDF15. GDF15 might be a promising target for clinical treatment of gastric cancer with CXXC4 deficiency.