Menin Coordinates C/EBPβ-Mediated TGF-β Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer
Menin Coordinates C/EBPβ-Mediated TGF-β Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer
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Menin 协调 C/EBPb 介导的 TGF-b 信号转导，促进胰腺癌上皮间质转化和生长抑制
DOI：
10.1016/j.omtn.2019.08.013
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发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Zhang, Yi-jie
中科院分区：
文献类型：
--
作者：
Cheng, Peng;Chen, Ying;Zhang, Yi-jie
Menin以上下文依赖的方式显示肿瘤抑制或促进功能。以前，我们提出Menin通过抑制胰腺导管腺癌（PDAC）中的细胞生长而充当肿瘤抑制因子，然而Menin表达与PDAC患者的总生存率之间的关系尚未完全阐明，表明Menin在PDAC进展中的功能的复杂性。在这里，我们确定Menin作为上皮间质转化（EMT）的启动子，这在很大程度上与细胞迁移或转移相关，在细胞生长抑制中具有适度的活性。Menin的异位表达通过组蛋白去乙酰化抑制CCAAT/增强子结合蛋白β（CEBPB）和上皮特异性基因的表达，并进一步增强TGF-β信号相关的EMT过程。我们还证明了CCAAT/增强子结合蛋白（C/EBP）β（C/EBP β;由CEBPB编码）在Menin和TGF-β信号传导的下游起平衡生长抑制和EMT的作用，并且C/EBP β过表达可以通过协同激活CDKN 2 A/B基因和拮抗EMT过程来恢复Menin在胰腺癌中的抗癌功能。综上所述，我们的研究结果表明，Menin作为癌基因的C/EBP β耗竭后的癌症转移或作为一个肿瘤抑制因子与C/EBP β合作，激活CDKN 2A转录。
Menin displays either tumor suppression or promotion functions in a context-dependent manner. Previously, we proposed that Menin acts as a tumor suppressor by inhibiting cell growth in pancreatic ductal adenocarcinoma (PDAC), whereas the relationship between the Menin expression and overall survival rate of PDAC patients has not been completely elucidated, indicating the complexity of Menin functions in PDAC progression. Here, we identify Menin as a promoter of epithelial-mesenchymal transition (EMT), which is largely associated with cell migration or metastasis, with modest activity in cell growth inhibition. Ectopic expression of Menin suppresses the expression of CCAAT/enhancer-binding protein beta (CEBPB) and epithelial-specific genes by histone deacetylation and further enhances the TGF-beta signaling-related EMT process. We also demonstrate that CCAAT/enhancer binding protein (C/EBP) beta (C/EBP beta; encoded by CEBPB) acts downstream of Menin and TGF-beta signaling for balancing growth inhibition and EMT, and C/EBP beta overexpression could restore the anticancer functions of Menin in pancreatic cancer by cooperatively activating CDKN2A/B genes and antagonizing EMT processes. Taken together, our results suggest that Menin functions as an oncogene for cancer metastasis upon C/EBP beta depletion or acts as a tumor suppressor by cooperation with C/EBP beta to activate CDKN2A transcription.