日本奈良科学技术研究所Eishou Matsuda小组的一项最新研究探明了Zbtb38转录激活XIAP调控发育和癌症中的细胞凋亡。2026年3月17日出版的《分子细胞生物学报》杂志发表了这项成果。

该研究组证明了锌指转录因子Zbtb38，一个细胞凋亡的负调节因子，在功能丧失和功能获得实验中调节XIAP的表达，而不考虑p53的表达。值得注意的是，XIAP过表达可以挽救Zbtb38敲低诱导的细胞凋亡，这表明Zbtb38相关的细胞凋亡至少部分依赖于XIAP。从机制上讲，Zbtb38与XIAP上游调控区域的E-box基序结合并激活其转录。在胚胎干细胞分化和胚胎发生过程中，Zbtb38缺失增加了细胞凋亡，降低了XIAP和Bcl-2的表达，强调了它们在这些过程中的功能相关性。对人类肿瘤数据集的分析显示ZBTB38和XIAP表达之间存在很强的正相关，ZBTB38水平升高与高级别恶性肿瘤相关。

此外，Zbtb38敲低诱导XIAP表达降低的癌细胞凋亡，与p53表达无关。总的来说，这些发现揭示了一个新的Zbtb38-XIAP轴，它在细胞分化、发育和肿瘤发生过程中调节细胞凋亡，并突出了其在XIAP驱动和p53缺陷肿瘤中的治疗潜力。

据了解，X连接的细胞凋亡抑制蛋白（XIAP）是细胞凋亡的关键抑制因子，对细胞分化、胚胎发生和癌症进展至关重要。然而，其上游监管机制仍然知之甚少。

附：英文原文

Title: Zbtb38 transcriptionally activates XIAP to regulate apoptosis in development and cancer

Author: Shigeoka, Toshiaki, Nagaoka, Hiroyuki, Nurulita, Nunuk Aries, Tada, Shogo, Bessho, Yasumasa, Ishida, Yasumasa, Matsuda, Eishou

Issue&Volume: 2026-03-17

Abstract: The X-linked inhibitor of apoptosis protein (XIAP) is a key suppressor of apoptosis, crucial for cellular differentiation, embryogenesis, and cancer progression. However, its upstream regulatory mechanisms remain poorly understood. Here, we demonstrate that the zinc finger transcription factor Zbtb38, a negative regulator of apoptosis, modulates XIAP expression in both loss- and gain-of-function experiments, irrespective of p53 expression. Notably, XIAP overexpression rescues the apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated apoptosis is at least partially XIAP-dependent. Mechanistically, Zbtb38 binds to E-box motifs within upstream regulatory regions of XIAP and activates its transcription. During embryonic stem cell differentiation and embryogenesis, Zbtb38 depletion increases apoptosis and reduces XIAP and Bcl-2 expression, underscoring their functional relevance in these processes. Analysis of human tumor datasets reveals a strong positive correlation between ZBTB38 and XIAP expression, with elevated ZBTB38 levels associated with high-grade malignancies. Furthermore, Zbtb38 knockdown induces apoptosis in cancer cells with reduced XIAP expression, regardless of p53 expression. Collectively, these findings uncover a novel Zbtb38–XIAP axis that regulates apoptosis during cellular differentiation, development, and oncogenesis and highlight its therapeutic potential in XIAP-driven and p53-deficient tumors.

DOI: 10.1093/jmcb/mjag011

Source: https://dx.doi.org/10.1093/jmcb/mjag011