Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy.

食管鳞状细胞癌（ESCC）是世界范围内最常见的人类恶性肿瘤之一，具有高发病率和死亡率。目前的治疗选择有限，凸显了开发新型有效药物的必要性。在这里，使用二维和三维培养系统中的 ESCC 细胞系进行高通量药物筛选 (HTS)，以筛选具有抗 ESCC 活性的化合物。我们的筛选确定了罗米地辛（一种组蛋白脱乙酰酶抑制剂）作为潜在的抗食管鳞癌药物。罗米地辛治疗降低了 ESCC 细胞系中的细胞活力，诱导细胞凋亡和细胞周期停滞，这些发现在 ESCC 细胞系来源的异种移植 (CDX) 小鼠模型中得到了证实。从机械角度来看，romidepsin 通过其启动子区域的组蛋白高度乙酰化诱导 DNA 损伤诱导转录物 4 (DDIT4)基因的转录上调，从而抑制哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 通路。此外，与传统治疗药物相比，罗米地辛在 ESCC 患者来源的异种移植（PDX）小鼠模型中表现出更好的疗效和安全性。这些数据表明罗米地辛可能是抗食管鳞癌治疗的新选择。