Master transcription factor reprograming unleashes selective translation promoting castration resistance and immune evasion in lethal prostate cancer.

Signaling rewiring allows tumors survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer (PCa) unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprograming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5'-UTRs. Indeed, translation of the androgen receptor (AR) and major histocompatibility complex I (MHC-I) through this motif are sensitive to eIF3B amount. Notably, pharmacological targeting of eIF3B-dependent translation in pre-clinical models sensitizes PCa to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy refractory lethal PCa and provide a druggable mechanism that may transcend into effective combined therapeutic strategies.