Zhang Li, Deng Lisheng, Chen Fengju, Yao Yuan, Wu Bulan, Wei Liping, Mo Qianxing, Song Yongcheng
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Oncotarget. 2014 Nov 15;5(21):10665-77. doi: 10.18632/oncotarget.2496.
Histone lysine methylation regulates gene expression and cancer initiation. Bioinformatics analysis suggested that DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, plays a potentially important role in breast cancer. DOT1L inhibition selectively inhibited proliferation, self-renewal, metastatic potential of breast cancer cells and induced cell differentiation. In addition, inhibitors of S-adenosylhomocysteine hydrolase (SAHH), such as neplanocin and 3-deazaneplanocin, also inhibited both H3K79 methylation and proliferation of breast cancer cells in vitro and in vivo. The activity of SAHH inhibitors was previously attributed to inhibition of H3K27 methyltransferase EZH2. However, inhibition of EZH2 by a specific inhibitor did not contribute to cell death. SAHH inhibitors had only weak activity against H3K27 methylation and their activity is therefore mainly due to DOT1L/H3K79 methylation inhibition. Overall, we showed that DOT1L is a potential drug target for breast cancer.
组蛋白赖氨酸甲基化调控基因表达及癌症起始。生物信息学分析表明，组蛋白H3赖氨酸79（H3K79）甲基转移酶DOT1L在乳腺癌中发挥潜在重要作用。DOT1L抑制可选择性抑制乳腺癌细胞的增殖、自我更新、转移潜能并诱导细胞分化。此外，S - 腺苷同型半胱氨酸水解酶（SAHH）抑制剂，如奈拉滨和3 - 去氮杂奈拉滨，在体外和体内均能抑制H3K79甲基化及乳腺癌细胞的增殖。SAHH抑制剂的活性此前被认为归因于对H3K27甲基转移酶EZH2的抑制。然而，特异性抑制剂对EZH2的抑制并不导致细胞死亡。SAHH抑制剂对H3K27甲基化仅有微弱活性，因此其活性主要归因于对DOT1L/H3K79甲基化的抑制。总体而言，我们表明DOT1L是乳腺癌的一个潜在药物靶点。
