Tan Jing, Yang Xiaojing, Zhuang Li, Jiang Xia, Chen Wei, Lee Puay Leng, Karuturi R K Murthy, Tan Patrick Boon Ooi, Liu Edison T, Yu Qiang
Molecular Pharmacology, Genome Institute of Singapore, 138672, Singapore.
Genes Dev. 2007 May 1;21(9):1050-63. doi: 10.1101/gad.1524107. Epub 2007 Apr 16.
Polycomb-repressive complex 2 (PRC2)-mediated histone methylation plays an important role in aberrant cancer gene silencing and is a potential target for cancer therapy. Here we show that S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) induces efficient apoptotic cell death in cancer cells but not in normal cells. We found that DZNep effectively depleted cellular levels of PRC2 components EZH2, SUZ12, and EED and inhibited associated histone H3 Lys 27 methylation (but not H3 Lys 9 methylation). By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, we have identified a prominent set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. We further demonstrate that the preferential reactivation of a set of these genes by DZNep, including a novel apoptosis affector, FBXO32, contributes to DZNep-induced apoptosis in breast cancer cells. Our results demonstrate the unique feature of DZNep as a novel chromatin remodeling compound and suggest that pharmacologic reversal of PRC2-mediated gene repression by DZNep may constitute a novel approach for cancer therapy.
多梳抑制复合物2（PRC2）介导的组蛋白甲基化在癌症相关基因异常沉默中起重要作用，是癌症治疗的潜在靶点。在此，我们表明S-腺苷同型半胱氨酸水解酶抑制剂3-去氮杂氮胞苷（DZNep）可诱导癌细胞发生高效凋亡，但对正常细胞无此作用。我们发现DZNep能有效降低细胞中PRC2组分EZH2、SUZ12和EED的水平，并抑制相关的组蛋白H3赖氨酸27甲基化（但不影响H3赖氨酸9甲基化）。通过整合RNA干扰（RNAi）、全基因组表达分析和染色质免疫沉淀（ChIP）研究，我们鉴定出一组在乳腺癌中被PRC2选择性抑制且可被DZNep重新激活的重要基因。我们进一步证明，DZNep对其中一组基因（包括一种新型凋亡影响因子FBXO32）的优先重新激活作用，有助于DZNep诱导乳腺癌细胞凋亡。我们的结果证明了DZNep作为一种新型染色质重塑化合物的独特特性，并表明通过DZNep对PRC2介导的基因抑制进行药理学逆转可能构成一种新的癌症治疗方法。
