Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer

Treatment-induced neuroendocrine prostate cancer (NEPC) represents an aggressive form of castration-resistant prostate cancer (CRPC) associated with lineage plasticity and therapeutic resistance. In this study, we investigated the role of the Hippo signaling axis in the transdifferentiation from androgen receptor-positive prostate cancer (ARPC) to NEPC. RNA sequencing analyses of CRPC metastases revealed coordinated alterations in Hippo pathway components, with decreased expression of YAP1, LATS2, and TEAD2 and increased expression of LATS1, TEAD1, and the RNA splicing regulator RBFOX2 in NEPC. These transcriptional alterations were consistently observed across multiple model systems and patient samples. Epigenetic analyses demonstrated that reduced expression of YAP1, TEAD2, and LATS2 was associated with increased DNA methylation, whereas elevated TEAD1 expression correlated with DNA hypomethylation in NEPC. NEPC selectively retained TEAD1 expression, including a spliced isoform not detected in ARPC. Proteomic interactome analyses revealed that TEAD1 associated with RNA splicing factors and DNA repair proteins. Functional studies showed that TEAD1 knockdown led to the reversion of gene programs associated with epithelial differentiation. These findings indicate that the conversion of ARPC to NEPC involves coordinated loss of AR, YAP1, and REST activity alongside sustained TEAD1 expression and altered RNA processing. Our data identify TEAD1 as a transcriptional regulator associated with the NEPC state and suggest a role for TEAD1-linked transcriptional and post-transcriptional mechanisms in prostate cancer lineage plasticity.