Wang Hongxiao, Song Zijun, Xie Enjun, Chen Junyi, Tang Biyao, Wang Fudi, Min Junxia
The First Affiliated Hospital, The Fourth Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China.
The First Affiliated Hospital, The Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China.
Research (Wash D C). 2022 Jun 1;2022:9814652. doi: 10.34133/2022/9814652. eCollection 2022.
Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both and . Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.
尽管最近在食管鳞状细胞癌（ESCC）的管理和治疗方面取得了进展，但其预后仍然极差，并且目前的非手术治疗选择有限。为了确定新的治疗靶点，我们使用一组癌细胞系筛选了一个经过整理的表观遗传化合物文库，发现同时抑制组蛋白去甲基化酶LSD1和组蛋白甲基转移酶G9a能有效抑制细胞生长；通过敲低LSD1和G9a的表达也获得了类似的结果。重要的是，我们还发现抑制LSD1和G9a显著降低了携带ESCC细胞系的异种移植小鼠模型中的肿瘤生长。为了检验这些发现的临床相关性，我们对从人食管鳞状癌组织获得的微阵列分析数据进行了免疫组织化学分析，发现与健康组织相比，LSD1和G9a在癌组织中均上调，并且这种表达增加与不良预后显著相关。从机制上讲，我们发现抑制LSD1和G9a通过S期阻滞和凋亡诱导细胞死亡，并且共同靶向内质网应激途径增强了这种效应。综上所述，这些发现提供了令人信服的证据，表明靶向LSD1、G9a和内质网应激相关途径可能是ESCC的一种可行治疗策略。
