Deletion of the ncPRC1 Subunit RYBP Located at 3p13 Epigenetically Reprograms Primary Prostate Cancer

Polycomb group (PcG) proteins form the Polycomb Repressive Complexes 1 and 2 (PRC1/2), which regulate gene expression through histone modifications. Their dysregulation is implicated in cancer. Genomic analysis of prostate cancer datasets revealed a striking divergence: PRC1 genes are frequently amplified in metastatic disease (SU2C), correlating with poor survival, higher tumor mutational burden (TMB), and enhanced androgen receptor (AR) signaling. In contrast, primary prostate cancer (PRAD) is characterized by recurrent deletion of the 3p13 locus, which harbors the gene for the non-canonical PRC1 subunit RYBP. Transcriptomic analysis indicated that RYBP loss derepresses gene expression, consistent with its role in transcriptional repression. Functionally, RYBP expression positively correlates with AR activity and negatively associates with neuroendocrine (NEPC) differentiation. Spatial and single-cell transcriptomics further show that RYBP is enriched in normal epithelial cells but downregulated in tumor cells. Besides, tumors with lower RYBP expression exhibit an immunosuppressive microenvironment, characterized by increased regulatory T cells. Collectively, these findings position RYBP deletion not only as a novel DNA-based biomarker for primary prostate cancer but also as a pivotal epigenetic deregulation event that coordinates oncogenic signaling and lineage plasticity.