Genetic loss of CHD1 regulates distinct histone post-translational modifications in the development of castration-resistant prostate cancer.

Overview

abstract

Epigenetic alterations accumulate with the development of castration resistance in prostate cancer (PC), yet an understanding of how these patterns arise remains incompletely defined. Through histone post-translational modification (PTMs) profiling in paired hormone-sensitive (HS) and castration-resistant (CR) patient-derived xenografts, we identified a novel chromatin state characterized by CHD1 deficiency and global reductions in H3.3K27 and H3.3K36 methylation, which occurred with castration resistance development. Compared to wildtype, CHD1-deficient tumors exhibited lower expression and enzymatic activity of the histone-modifying enzymes (HMEs) NSD2 and EZH2-key regulators of the altered histone PTM landscape. Gene expression analysis of human CRPC samples revealed strong positive correlations among CHD1, NSD2, and EZH2. CHD1 knockout (KO) in CRPC cell lines confirms reduced H3.3K27K36 methylation and downregulation of NSD2 and EZH2. Results from mechanistic studies support a process in which CHD1 occupancy at the promoter regions of NSD2 and EZH2 facilitates transcription via enhanced chromatin accessibility and increased deposition of the activating histone mark H3K4me3. In contrast, CHD1-KO led to promoter accumulation of repressive H3K27me3 modifications. CHD1-KO downregulates interferon (IFN) signaling, including viral mimicry and IFN-stimulated genes. Bulk RNA-sequencing and ChIP-qPCR analyses confirmed co-regulation of these genes by CHD1 and NSD2, coinciding with reduced H3K36me2 enrichment. Notably, this CHD1-deficient epigenetic state confers resistance to NSD2 inhibition. These findings highlight a previously unrecognized role in tumor resistance for CHD1 in modulating HMEs that may influence lineage plasticity as well as suggest new avenues for personalized therapeutic strategies targeting CHD1-specific epigenetic vulnerabilities.