Soluble Nucleoporin, sPOM121, promotes prostate cancer progression and immune evasion through direct promoter regulation at active transcriptional hubs [ATAC-seq]

The role of nucleoplasmic residing nucleoporins (NUPs) in solid tumors, including prostate cancer, remain unknown. Here we uncover the clinical relevance and mechanistic role of the off-pore NUP soluble POM121 (sPOM121) as a critical transcriptional regulator enhancing lethal prostate cancer aggressiveness. Mechanistically we found that sPOM121, through its C-terminal domain associates with the chromatin remodeler SMARCA5 at nuclear condensates facilitating transcriptional activation at promoter sites. Indeed, sPOM121 through this mechanism regulates a discrete oncogenic gene network, including B-catenin, leading to tumor progression and immune evasion in prostate cancer. Notably, targeting the sPOM121-B-catenin axis in patient derived pre-clinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances anti-tumor immunity. Together, our findings reveal previously unknown actionable transcriptional rewiring functions of the nucleoplasmic residing NUP, sPOM121, in solid tumors, promoting lethal prostate cancer.