Nebbioso Angela, Clarke Nicole, Voltz Emilie, Germain Emmanuelle, Ambrosino Concetta, Bontempo Paola, Alvarez Rosana, Schiavone Ettore M, Ferrara Felicetto, Bresciani Francesco, Weisz Alessandro, de Lera Angel R, Gronemeyer Hinrich, Altucci Lucia
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, 80138, Napoli, Italy.
Nat Med. 2005 Jan;11(1):77-84. doi: 10.1038/nm1161. Epub 2004 Dec 26.
Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.
染色质是一种动态的大分子结构，通过表观遗传修饰来调节特定基因的表达。染色质功能的改变会导致生长调节因子的异常表达，并最终可能引发癌症。许多人类疾病具有表观遗传学病因，这推动了“表观遗传学”疗法的发展。组蛋白去乙酰化酶抑制剂（HDACIs）在体外和体内均可诱导癌细胞而非正常细胞的增殖停滞、成熟和凋亡，目前正在进行临床试验测试。我们研究了这种肿瘤选择性背后的机制。我们报告称，HDACIs除了诱导p21表达外，还通过直接激活TNFSF10启动子来诱导TRAIL（Apo2L，TNFSF10）的表达，从而在急性髓系白血病（AML）细胞和AML患者的原始细胞中触发肿瘤选择性死亡信号。RNA干扰显示，p21、TRAIL的诱导和分化是HDACIs可分离的活性。HDACIs诱导增殖停滞、TRAIL介导的凋亡以及抑制AML原始细胞克隆形成能力，而与法美英（FAB）分类状态、核型和免疫表型无关。在正常CD34(+)祖细胞中未观察到凋亡。我们的结果确定TRAIL是HDACIs抗癌作用的介质。
