Zbtb38 inhibits apoptosis by transcriptionally regulating XIAP expression

X-linked inhibitor of apoptosis protein (XIAP) is a key suppressor of apoptosis, a major form of programmed cell death critical for cellular differentiation, embryogenesis, and cancer development. Despite its importance, the upstream regulators and regulatory elements of XIAP are not well understood. This study provides evidence that the zinc finger transcription factor Zbtb38, a negative regulator of apoptosis, regulates XIAP expression in Zbtb38 loss- and gain-of-function experiments. Notably, XIAP overexpression rescued the apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-mediated apoptosis is at least partially dependent on XIAP. Chromatin immunoprecipitation and luciferase assays revealed that Zbtb38 binds to and activates E-boxes within the XIAP enhancer, underscoring the critical role of these E-boxes in XIAP expression. Additionally, Zbtb38 loss during embryonic stem (ES) cell differentiation and embryogenesis resulted in increased apoptosis and decreased expression of XIAP and Bcl-2, highlighting their importance in these processes. Furthermore, Zbtb38 downregulation induced apoptosis in cancer cells lacking p53 expression, suggesting that Zbtb38 could be a potential therapeutic target in cancer.