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Targeting Chromatin Remodeling Complexes to Inhibit Oncogenic Androgen Receptor Activity in Prostate Cancer


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Successful development of second-generation AR targeting agents like enzalutamide and abiraterone significantly prolonged survival of mCRPC patients but are not curative due to the invariable development of resistance. During disease progression, prostate cancer cells adapt various mechanisms to maintain AR signaling, such as AR amplification/mutation and gain-of function of PCa-specific enhancers (neo-enhancers) to drive hyper-proliferation. This suggests that targeting of AR action at the level of chromatin remodeling and enhancer accessibility may be a viable treatment strategy for mCRPC, whereby enhancer activity and gene expression of AR targets could be transcriptionally repressed. In this study, we generated the SMARCA2/4 genetic inactivation PCa cell line model and confirmed the effect of dual degradation of SMARCA2/4 on hallmarks of PCa cells.Furthermore, by profiling SMARCA2/4 degradation-mediated changes of the chromatin accessibility/architecture, AR cistrome and transcriptome in AR-driven PCa cells, we ascertained that mSWI/SNF complexes, through dynamic maintenance of cancer-driving enhancers in accessible states and promoter-enhancer interaction, are essential for chromatin binding of the AR signaling complex. Therefore, degradation of the ATPases of mSWI/SNF complexes can significantly attenuate the proliferation and survival of mCRPC cells.



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