The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, China.
Cell Biochem Funct. 2018 Dec;36(8):398-407. doi: 10.1002/cbf.3359. Epub 2018 Nov 28.
Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose-dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53-independent manner. SIGNIFICANCE OF THE STUDY: In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti-proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti-proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC.
食管鳞状细胞癌（ESCC）是一种常见的恶性肿瘤，目前尚无有效的治疗方法。组蛋白去乙酰化酶抑制剂（HDACIs）已被证明是一类新兴的抗癌药物，可用于治疗多种血液系统和实体肿瘤。然而，HDACIs 对 ESCC 细胞的作用尚未得到研究。在这项研究中，最初通过分析 Broad-Novartis 癌症细胞系百科全书的 27 个 ESCC 细胞系的表达数据，发现 ESCC 细胞系中 HDAC 基因表达较高，因此认为 HDACIs 对 ESCC 具有抗癌活性。接下来，我们使用五种 ESCC 细胞系和一种正常永生化食管上皮细胞系，筛选了三种 HDACIs，panobinostat（LBH589）、vorinostat（SAHA）和 trichostatin A（TSA），以评估它们抑制生长的能力。在这里，我们报告 LBH589 比 TSA 和 SAHA 更有效地抑制 ESCC 细胞系的增殖，呈剂量依赖性，并且对 SHEE 正常永生化食管上皮细胞系的毒性较低。进一步的实验表明，LBH589 处理显著抑制了 TP53（突变 TP53）的表达，无论是在 mRNA 水平还是在蛋白水平，同时增加了 p21 的表达，降低了 cyclin D1 的表达。总之，我们提出 LBH589 主要通过增加 p21 和减少 cyclin D1 来诱导细胞周期停滞，从而抑制 ESCC 细胞的增殖，这种作用不依赖于 p53。
在这项研究中，我们对 ESCC 的 HDACIs LBH589、SAHA 和 TSA 的抗肿瘤活性进行了研究，LBH589 显示出最强的抗增殖活性，而对正常永生化食管上皮细胞没有损害。此外，我们提出 LBH589 通过诱导细胞周期停滞发挥其抗增殖作用。LBH589 能够特异性地靶向癌细胞，表明其在 ESCC 治疗中的潜在治疗价值。
