Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Cell. 2011 Sep 16;146(6):904-17. doi: 10.1016/j.cell.2011.08.017. Epub 2011 Sep 1.
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.
MYC 有助于大多数人类癌症的发病机制，但目前尚无调节 c-Myc 癌蛋白功能的策略。针对这一目标，我们通过干扰依赖染色质的信号转导到 RNA 聚合酶，特异性地抑制参与转录起始和延伸的假定共激活蛋白的乙酰-赖氨酸识别结构域（溴结构域），从而靶向 MYC 转录。我们使用一种选择性的小分子溴结构域抑制剂 JQ1，鉴定出 BET 溴结构域蛋白是 c-Myc 的调节因子。JQ1 通过 BET 抑制下调 MYC 转录，随后导致 Myc 依赖性靶基因的全基因组下调。在多发性骨髓瘤（一种 Myc 依赖性血液系统恶性肿瘤）的实验模型中，JQ1 产生强烈的抗增殖作用，伴有细胞周期停滞和细胞衰老。JQ1 在三种多发性骨髓瘤的小鼠模型中的疗效确立了 BET 溴结构域抑制在这种疾病和其他以 c-Myc 病理性激活为特征的恶性肿瘤中的治疗原理。
