Functional Characterization of eRNA Coregulator Interactions at AR Bound Enhancers in Advanced Therapy Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) which has relapsed after first line androgen deprivation therapy (ADT), known as ADT-Recurrent PCa (ADT-RPCa) is incurable and the lethal form of the disease. Second generation antiandrogens, such as enzalutamide and apalutamide, are often used to treat ADTRPCa but resistance to these drugs emerges within several months. Disease progression and the acquisition of therapy resistance in PCa is associated with changes in binding of the androgen receptor (AR) to its cis-regulatory enhancer elements. Enhancers, which regulate the rate of transcription by serving as nucleation sites for the binding of transcription factors, coregulators, RNA polymerase II and other regulatory proteins, were recently found to be transcribed, producing non-coding RNA molecules called enhancer RNA (eRNA) which are increasingly being recognized for their role in enhancer function. While eRNAs have been shown to be transcribed from critical AR-bound active enhancers, their role in AR-regulated gene expression and PCa progression remains largely unknown. This work seeks to address this issue by applying cross-platform genomic approaches to define roles for potentially oncogenic eRNA to sustain AR enhancer interactions and target gene expression. Here, we used Global run on (GRO) sequencing to identify differences in eRNA transcriptomes between isogenic pairs of enzalutamide sensitive and resistant prostate cancer cell lines. This was integrated with AR ChIP-seq and ChIA-PET datasets to annotate resistance-associated eRNAs potentially regulated by AR. Ongoing work aims to test the functional implications of expression of these eRNA on coregulator functions, AR signalling and prostate cancer cell growth. This work will ultimately provide new insights into functional interactions at enhancers most likely to contribute to therapy resistance in prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2024
- Accession Number
- AD1229236
Entities
People
- Rayzel Fernandes
Organizations
- Imperial College London