以胆固醇合成的表观遗传调控为靶点，作为头颈部鳞状细胞癌的治疗策略。
Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma.
机构信息
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
出版信息
Cell Death Dis. 2021 May 13;12(5):482. doi: 10.1038/s41419-021-03760-2.
The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.
组蛋白甲基转移酶 EZH2 通过 H3 赖氨酸 27 三甲基化沉默基因表达，已被认为是一种重要的抗肿瘤治疗靶点。然而，现有 EZH2 抑制剂在治疗实体瘤方面的临床应用并不令人满意。为了发现针对头颈部鳞状细胞癌 (HNSCC) 的新策略，我们对用 EZH2 抑制剂处理的 HNSCC 细胞进行了基因组学、代谢组学和 RNA 组学研究。结果发现，EZH2 抑制剂强烈诱导胆固醇合成基因的表达。通过广泛的药物筛选，我们发现抑制角鲨烯环氧化酶（内源性胆固醇合成的关键酶）可协同增加角鲨烯含量并增强 HNSCC 细胞对 EZH2 抑制剂的敏感性。我们的发现为开发治疗 HNSCC 的 EZH2 抑制剂新组合提供了实验和理论依据。
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