Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration
Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration
复制标题
溴结构域和末端蛋白抑制对 YAP/TAZ-Notch1-NICD 轴的抑制会损害肝再生
DOI：
10.7150/thno.33370
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Gong, Weihua
中科院分区：
文献类型：
--
作者：
Liu, Chen;Cheng, Xiawei;Gong, Weihua
背景和目的：控制肝再生的生物学机制仍不清楚。然而，这些机制是临床上值得注意的问题，影响肝脏手术、创伤性损伤、慢性感染或肝中毒引起的肝损失的治疗。越来越多的证据表明，各种生长因子、细胞因子和代谢信号通路影响肝脏的再生过程。我们的目的是研究溴结构域和末端外（BET）蛋白抑制对肝再生的影响及其机制。方法：我们研究了 BET 蛋白抑制剂 JQ1 在 70% 部分肝切除 (PH) 小鼠模型肝再生中的作用。我们评估了yes相关蛋白（YAP）/具有PDZ结合基序（TAZ）和Notch信号通路的转录共激活因子，这些通路在体内小鼠肝组织和原代肝细胞以及体外AML12细胞系中受到BET蛋白抑制剂的影响。我们使用 YAP/TAZ 通路抑制剂在体内肝再生中评估了 YAP/TAZ 和 Notch 信号通路的关系。此外，我们通过 AML12 细胞中 Yap 的过表达或 RNA 沉默来分析 YAP/TAZ 和 Notch 信号通路的关系。此外，我们使用 Yap 过表达小鼠模型来检验它是否可以挽救因抑制 BET 蛋白而引起的肝再生损伤。结果：在这项研究中，我们报告 BET 蛋白抑制剂 JQ1 分子会损害 70% PH 后小鼠模型的早期肝再生。从机制上讲，体内小鼠肝组织和原代肝细胞以及体外小鼠AML12细胞系中的YAP/TAZ和Notch1-NICD通路被BET蛋白抑制剂抑制。通过使用YAP/TAZ通路抑制剂，我们证实体内YAP/TAZ通路的抑制会损害肝脏再生和Notch通路的激活。此外，研究表明，在正常小鼠肝细胞系中，shRNA 敲低 Yap 会下调 Notch1 信号转导，而 Yap 过表达则会促进 Notch1-NICD 信号。在小鼠肝脏中特异性过表达 Yap 可以挽救 BET 蛋白抑制对肝再生损伤的影响。结论：这些结果揭示了 YAP/TAZ-Notch1-NICD 轴在肝再生中的关键作用。因此，BET蛋白抑制剂由于其对肝再生的抑制作用，在治疗肝病时必须谨慎使用。
Background and aims: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro. We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro. By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. Conclusion: These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.