BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer
BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer
复制标题
BDH2 通过促进胃癌中 Nrf2 泛素化触发 ROS 诱导的细胞死亡和自噬
DOI：
10.1186/s13046-020-01620-z
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发表时间：
2020-06-30
影响因子：
11.3
通讯作者：
Xue, Wan-Jiang
中科院分区：
文献类型：
--
作者：
Liu, Jia-Zhou;Hu, Yi-Lin;Xue, Wan-Jiang
研究背景3-羟基丁酸脱氢酶2（3-Hydroxy butyrate dehydrogenase 2，BDH 2）是一种短链脱氢酶/还原酶家族成员，在人类肿瘤的发生和发病中起着关键作用。然而，BDH 2在胃癌（GC）中的作用仍不清楚。本研究旨在探讨BDH 2在胃癌中的调控机制，为胃癌的治疗提供新的思路。方法采用Western blotting、免疫组化和RT-PCR方法检测BDH 2在胃癌组织和胃癌细胞株中的表达。分析其与胃癌临床病理特征及预后的关系。进行功能测定，如CCK-8和TUNEL测定、透射电子显微镜和体内肿瘤生长测定，以检查GC细胞的增殖、凋亡和自噬。结果BDH 2在胃癌组织和细胞中表达明显下调，BDH 2的低表达与胃癌患者的生存率相关。在功能上，BDH 2过表达在体外和体内显著诱导细胞凋亡和自噬。BDH 2促进Keap 1与Nrf 2的相互作用，从而增加Nrf 2的泛素化水平。Nrf 2的泛素化/降解抑制ARE活性，增加活性氧（ROS）的积累，从而抑制AktSer 473和mTORSer 2448的磷酸化水平。结论BDH 2是胃癌重要的抑癌基因。BDH 2通过Keap 1/Nrf 2/ARE信号通路调节细胞内ROS水平，介导PI 3 K/Akt/mTOR通路，从而抑制GC的生长。
Background3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies.MethodsWestern blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays.ResultsBDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of AktSer473and mTORSer2448.ConclusionsOur study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.