Identification of regulatory system for cancer stemness and pplication to cancer therapeutics.

由组蛋白甲基转移酶驱动的甲基化事件与基因沉默和致癌有关。我们专注于与癌症干细胞相关的组蛋白甲基转移酶。在这个项目中，我们发现KLF2的表观遗传沉默发生在癌细胞中，通过组蛋白甲基转移酶，Zeste Homolog 2增强子（EZH2）介导的直接转录抑制。在ezh2相关沉默的细胞中转染KLF2，在培养和异种移植的裸鼠中均显示出显著的抗肿瘤作用。最重要的是，将上述结果转化为人类原发样本表明，患有低水平KLF2和高表达EZH2的前列腺或乳腺肿瘤患者的总生存期较短。此外，KLF2调节癌细胞的干性表型。最后，通过基于细胞的高通量筛选系统，我们发现了一个低分子量的化合物，可以诱导KLF2基因的表达。

Methylation events driven by histone methyltransferases have been implicated in gene silencing and carcinogenesis. We focused on histone methyltransferases related to cancer stemness. In this project, we show that epigenetic silencing of KLF2 occurs in cancer cells through direct transcriptional repression mediated by the histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2). The transfection of KLF2 in cells with EZH2-associated silencing showed a significant anti-tumoral effect, both in culture and in xenografted nude mice. Most importantly, the translation of the described results to human primary samples demonstrated that patients with prostate or breast tumors with low levels of KLF2 and high expression of EZH2 had a shorter overall survival. Moreover, KLF2 regulates stemness phenotype for cancer cells. Finally, we find a low molecular weight compound, which induces KLF2 gene expression using cell-based high-throughput screening system.