Restoration of p53 acetylation by HDAC inhibition permits the necrosis/apoptosis switch of pancreatic ainar cell during experimental pancreatitis in mice
Restoration of p53 acetylation by HDAC inhibition permits the necrosis/apoptosis switch of pancreatic ainar cell during experimental pancreatitis in mice
复制标题
在小鼠实验性胰腺炎期间，通过 HDAC 抑制恢复 p53 乙酰化允许胰腺细胞坏死/凋亡转换。
DOI：
10.1002/jcp.28761
复制
发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Wan, Rong
中科院分区：
文献类型：
--
作者：
Hu, Yangyang;Dai, Juanjuan;Wan, Rong
急性胰腺炎（AP）的严重程度很大程度上归因于胰腺腺泡细胞（PAC）的死亡反应。研究表明，细胞凋亡诱导疗法对实验性胰腺炎具有保护作用，具有很大的临床治疗潜力。然而，目前针对AP期间细胞凋亡的药物在很大程度上缺乏特异性。因此，揭示控制腺泡细胞死亡的具体机制仍然是必要的。PAC的死亡反应表现为小鼠AP过程中进行性坏死伴凋亡沉默。在本研究中，我们发现p53的转录活性受损，其促凋亡靶点Puma和CD95的表达显著降低，这可以解释AP期间的凋亡沉默。此外，我们发现p53的功能抑制是由组蛋白去乙酰化酶（HDAC）介导的PAC中p53 c端去乙酰化引起的。导致坏死/凋亡开关，并保护小鼠免受cerulein或l- arg诱导的AP。我们的研究发现hdac依赖的p53活性调节是腺泡细胞死亡反应的关键机制，它代表了治疗AP的特定靶点。
The severity of acute pancreatitis (AP) is greatly attributed to the pancreatic acinar cell (PAC) death response. It has been established that the apoptosis-inducing therapy can protect against experimental pancreatitis and have great clinical therapeutic potential. However, current pharmacologic agents that target apoptosis during AP largely lack specificity. Thus, it remains imperative to reveal the specific mechanisms governing acinar cell death. Death responses of PAC are manifested by the progressive necrosis accompanied by apoptosis silencing during AP in mice. In this study, we found that the transcriptional activity of p53 was impaired and the expressions of its proapoptotic targets Puma and CD95 were significantly decreased, which explains the apoptosis silencing during AP. Furthermore, we found that the functional depression of p53 was resulted from histone deacetylase (HDAC)-mediated deacetylation of p53 C-terminal in PAC during AP. Treatment of the HDAC inhibitor trichostatin-A restored p53 apoptosis pathway, resulted in a necrosis/apoptosis switch and protected mice from cerulein- or l-Arg-induced AP. Our research identified the HDAC-dependent regulation of p53 activity as a critical mechanism underlying acinar cell death response, which represents a specific target for the treatment of AP.