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癌症的发生有关。我们的重点是与癌症干细胞有关的组蛋白甲基转移酶。在这个项目中，我们证明了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Zust Homolog 2增强子(EZH2)介导的直接转录抑制。将KLF2基因导入EZH2相关沉默的细胞中，无论是在培养中还是在裸鼠移植瘤中，都显示出显著的抗肿瘤作用。最重要的是，将所描述的结果翻译到人类原始样本中表明，KLF2水平低而EZH2高表达的前列腺癌或乳腺肿瘤患者的总生存期较短。此外，KLF2还调节癌细胞的干性表型。最后，利用基于细胞的高通量筛选系统，我们找到了一个诱导KLF2基因表达的低分子量化合物。

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.