Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer
Abstract
Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine-N-methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth in vitro and in vivo better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 15, 2018
- Source ID
- 10.1158/0008-5472.can-18-0941
Entities
People
- A. Robert Macleod
- Abhijit Parolia
- Ajjai S. Alva
- Alice Xu
- Andrew Delekta
- Arul Chinnaiyan
- Esther Luo
- Fengyun Su
- Heng Zheng
- Jean C. Tien
- Josh Vo
- Kristin M. Juckette
- Lanbo Xiao
- Lisha Wang
- Mengyao Tan
- Sudhanshu Shukla
- Xiaoju Wang
- Xiaojun Jing
- Xuhong Cao
- Yajia Zhang
- Youngsoo Kim
- Yuanyuan Qiao
Organizations
- American Cancer Society
- Howard Hughes Medical Institute
- Indian Institute of Technology Dharwad
- Prostate Cancer Foundation
- United States Department of Defense
- University of Michigan