Bosco-Clément G, Zhang F, Chen Z, Zhou H-M, Li H, Mikami I, Hirata T, Yagui-Beltran A, Lui N, Do H T, Cheng T, Tseng H-H, Choi H, Fang L-T, Kim I-J, Yue D, Wang C, Zheng Q, Fujii N, Mann M, Jablons D M, He B
Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Tsinghua University Graduate School at Shenzhen, Division of Life and Health Sciences, Shenzhen, China.
Oncogene. 2014 Apr 17;33(16):2087-97. doi: 10.1038/onc.2013.164. Epub 2013 May 20.
Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.
在临床前和早期临床研究中，靶向抑制细胞膜上的刺猬信号通路已显示出抗癌活性。刺猬信号通路涉及Gli转录因子的激活，而Gli转录因子也可由其他途径诱导产生。在本研究中，我们鉴定了Gli蛋白与转录共激活因子TBP相关因子9（TAF9）之间的相互作用，并验证了其在调节Gli反式激活中的功能相关性。我们还描述了一种新型合成小分子FN1-8，它能有效干扰Gli/TAF9相互作用，并下调Gli/TAF9依赖的转录活性。更重要的是，FN1-8在体外抑制癌细胞增殖，在体内抑制肿瘤生长。我们的结果表明，阻断Gli反式激活这一多种致癌途径的重要控制点，可能是一种有效的抗癌策略。
