Abstract
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.
Highlights
Despite recent advances in diagnosis and treatment, gastric cancer remains the fourth most common cancer worldwide [1] and the second leading cause of cancer deaths [2,3,4]
We recently found that tumor suppressor CXXC finger protein 4 (CXXC4) was downregulated in gastric cancer and its downregulation was associated with a poor prognosis in gastric cancer patients [9]
We found in this report that CXXC4 located in the nucleus and was able to stimulate the transcription of Growth differentiation factor 15 (GDF15) to activate apoptosis
Summary
Despite recent advances in diagnosis and treatment, gastric cancer remains the fourth most common cancer worldwide [1] and the second leading cause of cancer deaths [2,3,4]. Aberrant activation of oncogenes and inactivation of tumor suppressor genes eventually altered signaling pathways critical for cell proliferation, differentiation, cell cycle and cell fate decision in gastric cancer [5,6,7,8]. We recently found that tumor suppressor CXXC finger protein 4 (CXXC4) was downregulated in gastric cancer and its downregulation was associated with a poor prognosis in gastric cancer patients [9]. It was directly regulated by EZH2 and functioned to negatively regulate Wnt/β-catenin and Ras/MAPK signaling [9,10,11,12]. We found in this report that CXXC4 located in the nucleus and was able to stimulate the transcription of GDF15 (growth differentiation factor 15) to activate apoptosis
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