Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells
Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells
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DOI：
10.1007/s00418-021-01966-1
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发表时间：
2021-05
影响因子：
2.3
通讯作者：
Yuma Shindo;W. Arai;Takumi Konno;Takayuki Kohno;Yuki Kodera;H. Chiba;M. Miyajima;Y. Sakuma;
中科院分区：
文献类型：
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作者：
Yuma Shindo;W. Arai;Takumi Konno;Takayuki Kohno;Yuki Kodera;H. Chiba;M. Miyajima;Y. Sakuma;
组蛋白去乙酰化酶（HDAC）抑制剂对非小细胞肺癌（NSCLC）具有潜在的治疗作用。然而，需要更多的HDAC抑制剂在NSCLC和正常肺上皮细胞中的临床前研究来评估其抗肿瘤活性和机制。双细胞紧密连接分子claudin-2（CLDN-2）在肺腺癌组织中高度表达，并促进肺腺癌细胞增殖。下调三细胞紧密连接分子angulin-1/LSR通过EGF依赖性CLDN-2和TGF-β依赖性细胞代谢诱导人肺腺癌细胞恶性肿瘤在本研究中，为了研究HDAC抑制剂在肺腺癌中的抗肿瘤活性的详细机制，用HDAC抑制剂曲古抑菌素A（TSA）和Quisinostat（JNJ-2648158）与或不与TGF-β一起处理人肺腺癌A549细胞和正常肺上皮细胞。两种HDAC抑制剂均能增加anguin-1/LSR，降低CLDN-2，促进A549细胞G1期阻滞，抑制其迁移。此外，TSA而非Quisinostat在有或没有TGF-β的情况下诱导的细胞代谢指示为使用耗氧速率测量的线粒体呼吸。在正常人肺上皮细胞中，TSA和Quisinostat处理增加了LSR和CLDN-2的表达，并降低了2D培养中有或没有TGF-β的CLDN-1的表达。Quisinostat而不是TSA与TGF-β增加了2D培养中CLDN-7的表达。两种HDAC抑制剂均防止上皮屏障的破坏，所述上皮屏障被测量为在2.5D培养物中由TGF-β诱导的FD-4的渗透性。TSA和Quisinostat具有通过改变angulin-1/LSR和CLDN-2的表达用于治疗肺腺癌的潜力。
Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for non-small cell lung cancer (NSCLC). However, more preclinical studies of HDAC inhibitors in NSCLC and normal lung epithelial cells are required to evaluate their antitumor activities and mechanisms. The bicellular tight junction molecule claudin-2 (CLDN-2) is highly expressed in lung adenocarcinoma tissues and increase the proliferation of adenocarcinoma cells. Downregulation of the tricellular tight junction molecule angulin-1/LSR induces malignancy via EGF-dependent CLDN-2 and TGF-β-dependent cellular metabolism in human lung adenocarcinoma cells. In the present study, to investigate the detailed mechanisms of the antitumor activities of HDAC inhibitors in lung adenocarcinoma, human lung adenocarcinoma A549 cells and normal lung epithelial cells were treated with the HDAC inibitors Trichostatin A (TSA) and Quisinostat (JNJ-2648158) with or without TGF-β. Both HDAC inhibitors increased anguin-1/LSR, decrease CLDN-2, promoted G1 arrest and prevented the migration of A549 cells. Furthermore, TSA but not Quisinostat with or without TGF-β induced cellular metabolism indicated as the mitochondrial respiration measured using the oxygen consumption rate. In normal human lung epithelial cells, treatment with TSA and Quisinostat increased expression of LSR and CLDN-2 and decreased that of CLDN-1 with or without TGF-β in 2D culture. Quisinostat but not TSA with TGF-β increased CLDN-7 expression in 2D culture. Both HDAC inhibitors prevented disruption of the epithelial barrier measured as the permeability of FD-4 induced by TGF-β in 2.5D culture. TSA and Quisinostat have potential for use in therapy for lung adenocarcinoma via changes in the expression of angulin-1/LSR and CLDN-2.