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.
Cancer cell. 2017 Mar 23 [Epub]
Xiaoju Wang, Yuanyuan Qiao, Irfan A Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cieślik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V S K Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X Wang, Ingrid J Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally, Arul M Chinnaiyan
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., 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; Department of Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India., 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 Alabama at Birmingham, Birmingham, AL 35233, USA., Department of Biostatistics, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Center for Computational Medicine and Bioinformatics, 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 Internal Medicine, 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; Department of Pharmacology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, 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; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, 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; Howard Hughes Medical Institute, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Urology, 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. Electronic address: .