食管癌是高度侵袭性肿瘤,预后差,尽管最近在手术和放化疗治疗选择方面取得了一些进展。这项研究探讨了针对食管鳞状细胞癌(ESCC)和食管腺癌(EAC)细胞的表观遗传修饰剂的药物的可行性。我们测试了SAHA对组蛋白脱乙酰酶(HDACs)的抑制作用,MS-275和FK228,氮杂胞苷(AZA)和地西他滨(DAC)对DNA甲基转移酶的抑制作用,以及两种药物联合治疗的效果。药物的目标,HDAC1/2/3和DNMT1在ESCC或EAC组织标本的正常食管上皮和肿瘤细胞中表达,以及在非肿瘤性食管上皮(Het-1A)中,ESCC(OE21,Kyse-270,Kyse-410),和EAC(OE33,SK-GT-4)细胞系。体外,HDAC活性,组蛋白乙酰化,和p21表达在非肿瘤中也受到类似的影响,ESCC,和EAC细胞系在抑制剂处理后。MS-275/AZA联合治疗,然而,通过诱导DNA损伤选择性靶向食管癌细胞系,细胞活力丧失,和细胞凋亡,通过减少细胞迁移。保护非肿瘤性Het-1A细胞免受HDACi(MS-275)/AZA处理。MS-275和/或AZA处理后的RNA转录组分析确定了新的受调控的候选基因(上:BCL6,Hes2;下:FAIM,MLKL),这与食管癌细胞的治疗反应特别相关。总之,HDACi/AZA联合治疗对于靶向食管癌细胞是有效和选择性的,尽管正常和食管癌上皮的靶表达相似,体外和人食管癌。治疗反应的确切作用机制涉及食管癌细胞中HDACi/AZA调控的新候选基因。一起,食道癌中表观遗传修饰剂的靶向可能代表一种潜在的未来治疗方法.
Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.