The YAP1-NPM1 nuclear complex regulates MYC and reveals a targetable oncogenic node.

Yes-associated protein 1 (YAP1) and nucleophosmin 1 (NPM1) regulate diverse cellular functions; however, their cooperative roles in cancer remain unclear. Here, we demonstrate that YAP1 and NPM1 form a direct nuclear protein complex in prostate cancer cells and tissues, as revealed by proteomics, co-immunoprecipitation, proximity ligation, and GST-pulldown assays. Androgen signaling modulates the YAP1-NPM1 interaction in androgen receptor-positive cells. Genetic or pharmacologic inhibition of NPM1 disrupts YAP1-NPM1 protein assembly, decreases YAP1 and MYC expression, and suppresses cell proliferation and motility. Immunological and computational analyses of prostate tumor samples indicate that elevated YAP1 and NPM1 expression and interaction correlate with disease progression. These findings identify the YAP1-NPM1 axis as a key regulatory node that integrates oncogenic transcriptional programs and confers therapeutic vulnerabilities. Targeting this axis may enhance the efficacy of androgen receptor-directed therapies and provide new strategies for treating advanced prostate cancer.