Wang Xiaoju, Qiao Yuanyuan, Asangani Irfan A, Ateeq Bushra, Poliakov Anton, Cieślik Marcin, Pitchiaya Sethuramasundaram, Chakravarthi Balabhadrapatruni V S K, Cao Xuhong, Jing Xiaojun, Wang Cynthia X, Apel Ingrid J, Wang Rui, Tien Jean Ching-Yi, Juckette Kristin M, Yan Wei, Jiang Hui, Wang Shaomeng, Varambally Sooryanarayana, Chinnaiyan Arul M
Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
Cancer Cell. 2017 Apr 10;31(4):532-548.e7. doi: 10.1016/j.ccell.2017.02.017. Epub 2017 Mar 23.
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.
转录因子在多种癌症的发展中起关键作用，针对它们进行治疗性靶向仍然是一项挑战。在前列腺癌中，编码转录因子ERG的基因经常发生重排，并在前列腺肿瘤发生中起关键作用。在此，我们鉴定出了一系列与ERG的DNA结合结构域特异性相互作用的肽。ERG抑制肽（EIPs）及其衍生的拟肽以高亲和力和特异性结合ERG，导致ERG蛋白的蛋白水解降解。EIPs减弱了ERG介导的转录、染色质募集、蛋白质-蛋白质相互作用、细胞侵袭和增殖以及肿瘤生长。因此，对转录因子融合产物进行拟肽靶向可能为前列腺癌以及其他恶性肿瘤提供一种有前景的治疗策略。
