Targeting Chromatin Remodeling Complexes to Inhibit Oncogenic Androgen Receptor Activity in Prostate Cancer
Abstract
The development of second-generation AR-targeting agents, such as enzalutamide and abiraterone, has notably extended the lifespan of mCRPC patients. However, they aren't curative due to the inevitable emergence of resistance. As the disease advances, prostate cancer cells employ various tactics to sustain AR signaling, including AR amplification/mutation and the activation of prostate cancer-specific enhancers (neo-enhancers), leading to aggressive cell growth. This highlights the potential of targeting AR action by focusing on chromatin restructuring and enhancer accessibility as a therapeutic approach for mCRPC. Such strategies could dampen enhancer activity and repress the gene expression of AR targets. In our research, we established a SMARCA2/4 genetic inactivation model in PCa cell lines and verified the impact of simultaneous degradation of SMARCA2/4on key prostate cancer cell characteristics. Additionally, through a detailed analysis of changes in chromatin accessibility, AR cistrome, and transcriptome due to SMARCA2/4 degradation in AR-driven PCa cells, we determined that mSWI/SNF complexes are crucial. These complexes maintain cancer-promoting enhancers in accessible states and facilitate promoter-enhancer interactions, which are vital for the binding of the AR signaling complex to chromatin. Consequently, targeting the ATPases of mSWI/SNF complexes can significantly hinder the growth and survival of mCRPC cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1215471
Entities
People
- Abhijit Parolia
- Lanbo Xiao
- Yuanyuan Qiao
Organizations
- University of Michigan