Chromatin remodeling restraints oncogenic functions in prostate cancer

Primary prostate cancer (PCa) is characterized by multifocal growth and a highly variable clinical course, which is not effectively predicted by prognostic screenings. Innovative strategies for the stratification of primary prostate cancers are still needed. Using prostate biopsies, we analyzed the epigenome of 17 chemo-naïve patients with putative PCa for genome-wide mapping of heterochromatic and euchromatic domains, as well as their three-dimensional (3D) compartmentalization in the cell nucleus. We identified two subgroups of cancer patients with different degrees of chromatin 3D architecture and transcriptome alterations: the LDD (Low Degree of Decompartmentalization) and HDD (High Degree of Decompartmentalization) groups. HDD subtype exhibits an extensive chromatin reorganization that restrains tumor potential, by repressing pathways related to extracellular matrix remodeling and phenotypic plasticity. We derived an 18-genes transcriptional signature that distinguishes HDD from LDD subtype and we confirmed its prognostic relevance across multiple cohorts covering more than 900 prostate cancer patients in total. We propose this transcriptional signature derived from chromatin compartmentalization analysis as a novel prognostic tool that could be adopted at the time of the diagnostic prostate biopsy.