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.

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，需要对非小细胞肺癌和正常肺上皮细胞中的 HDAC 抑制剂进行更多的临床前研究，以评估其抗肿瘤活性和机制。双细胞紧密连接分子claudin-2（CLDN-2）在肺腺癌组织中高表达并增加腺癌细胞的增殖。三细胞紧密连接分子angulin-1/LSR的下调通过人肺腺癌细胞中依赖EGF的CLDN-2和依赖TGF-β的细胞代谢诱导恶性肿瘤。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) 在有或没有 TGF-β 的情况下处理人肺腺癌 A549 细胞和正常肺上皮细胞。两种 HDAC 抑制剂都增加了 anguin-1/LSR，减少了 CLDN-2，促进了 G1 期阻滞并阻止了 A549 细胞的迁移。此外，TSA 但不是 Quisinostat 有或没有 TGF-β 诱导的细胞代谢表明使用耗氧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 CLDN-1 在 2D 培养中存在或不存在 TGF-β 的表达。Quisinostat 而非 TSA 与 TGF-β 增加了二维培养中 CLDN-7 的表达。两种 HDAC 抑制剂都阻止了上皮屏障的破坏，测量为 2.5D 培养中 TGF-β 诱导的 FD-4 通透性。TSA 和 Quisinostat 有可能通过改变 angulin-1/LSR 和 CLDN-2 的表达用于治疗肺腺癌。