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Abstract

Next-generation androgen receptor (AR) pathway inhibitors (ARPIs) have been very successful at prolonging the life of men with prostate cancer. However, all patients will eventually become resistant, with roughly 20% of tumors displaying a lineage conversion from the typical AR-driven prostate adenocarcinoma (PRAD) to the particularly lethal neuroendocrine prostate cancer (NEPC) subtype. Notably, the mutational landscape of PRAD and NEPC is quite similar – only differing in frequency of TP53 and RB1 alterations – suggesting that epigenetic changes drive the lineage conversion. The objective was to explore the changing landscape of active epigenetic marks to gain an understanding of the lineage conversion process. I hypothesized that lineage plasticity involved significant remodeling of active histone post-translational modifications (PTMs). We performed ChIP-seq for H3K4me3 and H3K27ac histone marks to profile the promoter and enhancer landscapes in a variety of PCa models spanning different stages of lineage conversion to NEPC. I employed a comprehensive suite of omics-analysis tools, integrating ChIP-seq, ATAC-seq, and RNA-seq data from diverse PCa models, and patient samples to establish correlations between epigenetic alterations and changes in gene expression. My data indicated that active promoter marks are largely similar between PCa phenotypes. H3K4me3 marks at NEPC lineage gene promoters are already present in PRAD cells, whereas PRAD lineage gene promoters mostly retain their H3K4me3 marks in NEPC. I showed that most differentially expressed genes are associated with phenotype specific changes in H3K27ac marked enhancers. Unsupervised hierarchical clustering identified clusters of super-enhancers (SEs) with distinct activity dynamics during lineage plasticity. SE clusters were predictive of lineage conversion, and ARPI resistance. Lastly, I showed that the MYC-MAD-MAX family is enriched at plasticity associated SE regions. I also observed an expansion of MAX binding sites without MYC in NEPC, and showed that it regulates a subset of SEs by recruiting the HIRA histone chaperone complex. My results suggest that MAX reprogramming during lineage plasticity, promotes epigenomic remodeling by recruiting HIRA to regulate plasticity associated genes. This work improves our understanding of the changing histone PTMs landscape during lineage plasticity, and suggests the importance of targeting the MYC-MAD-MAX family to overcome treatment resistance.