Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China.
Department of Respiratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China.
Int J Oncol. 2019 Mar;54(3):1112-1122. doi: 10.3892/ijo.2019.4682. Epub 2019 Jan 9.
Plakoglobin is a tumor suppressor gene in lung cancer; however, the mechanism by which it is downregulated in lung cancer is largely unknown. The aim of the present study was to investigate whether histone deacetylases (HDACs) regulate plakoglobin expression in lung cancer. The effects of overexpression or knockdown of HDAC7 on plakoglobin were determined using stably transfected lung cancer cell lines. Chromatin immunoprecipitation assays were performed to elucidate the mechanisms underlying the HDAC7‑induced suppression of plakoglobin. A Cell Counting Kit‑8 and Transwell assays were performed, and a nude mouse in vivo model was established to investigate the role of the HDAC7/plakoglobin pathway in cell migration, invasion and metastasis. Ectopic expression of HDAC7 was identified to suppress mRNA and protein levels of plakoglobin in lung cancer cells, whereas silencing HDAC7 with short hairpin RNA increased the expression of plakoglobin. HDAC7 was proposed to suppressed plakoglobin by directly binding to its promoter. Overexpression or knockdown of HDAC7 promoted or inhibited cell proliferation, migration and invasion, respectively. Furthermore, knockdown of HDAC7 significantly suppressed tumor growth and metastasis in vivo. In addition, overexpression of plakoglobin significantly reduced the enhanced cell proliferation, migration and invasion induced by ectopic HDAC7. In conclusion, suppression of plakoglobin by HDAC7 promoted the proliferation, migration, invasion and metastasis in lung cancer. This novel axis of HDAC7/plakoglobin may be valuable in the development of novel therapeutic strategies for treating patients with lung cancer.
桥粒芯糖蛋白是肺癌中的抑癌基因；然而，其在肺癌中下调的机制在很大程度上尚不清楚。本研究旨在探讨组蛋白去乙酰化酶（HDACs）是否调节肺癌中的桥粒芯糖蛋白表达。使用稳定转染的肺癌细胞系确定过表达或敲低 HDAC7 对桥粒芯糖蛋白的影响。通过染色质免疫沉淀实验阐明了 HDAC7 诱导的桥粒芯糖蛋白抑制的机制。进行细胞计数试剂盒-8 检测和 Transwell 检测，建立裸鼠体内模型，以研究 HDAC7/桥粒芯糖蛋白通路在细胞迁移、侵袭和转移中的作用。研究表明，外源表达 HDAC7 可抑制肺癌细胞中桥粒芯糖蛋白的 mRNA 和蛋白水平，而用短发夹 RNA 沉默 HDAC7 则增加桥粒芯糖蛋白的表达。HDAC7 通过直接结合其启动子抑制桥粒芯糖蛋白的表达。HDAC7 的过表达或敲低分别促进或抑制细胞增殖、迁移和侵袭。此外，沉默 HDAC7 可显著抑制体内肿瘤生长和转移。此外，过表达桥粒芯糖蛋白可显著降低由外源性 HDAC7 引起的增强的细胞增殖、迁移和侵袭。总之，HDAC7 对桥粒芯糖蛋白的抑制促进了肺癌中的增殖、迁移、侵袭和转移。HDAC7/桥粒芯糖蛋白这一新型轴可能对开发治疗肺癌患者的新型治疗策略具有重要价值。
