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.
Cancer discovery. 2023 Sep 07 [Epub ahead of print]
Sandra Santasusagna, Shijia Zhu, Vijayakumar Jawalagatti, Marc Carceles-Cordon, Adam Ertel, Saioa Garcia-Longarte, Won-Min Song, Naoto Fujiwara, Peiyao Li, Isabel Mendizabal, Daniel P Petrylak, William Kevin Kelly, E Premkumar Reddy, Liguo Wang, Matthew J Schiewer, Amaia Lujambio, Jeffrey Karnes, Karen E Knudsen, Carlos Cordon-Cardo, Haidong Dong, Haojie Huang, Arkaitz Carracedo, Yujin Hoshida, Veronica Rodriguez-Bravo, Josep Domingo-Domenech
Mayo Clinic, Rochester, MN, United States., University of Minnesota, Minneapolis, MN, United States., Thomas Jefferson University, Philadelphia, PA, United States., Thomas Jefferson University, Philadelphia, Pennsylvania, United States., Center for Cooperative Research in Biosciences, Bilbao, Spain., Icahn School of Medicine at Mount Sinai, New York, NY, United States., The University of Tokyo, Tokyo, Japan., Yale Cancer Center, New Haven, Connecticut, United States., Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, United States., Icahn School of Medicine at Mount Sinai, New York, United States., Sidney Kimmel Cancer Center at Jefferson Health, Philadelphia, PA, United States., CIC bioGUNE, Derio, Vizcaya, Spain., The University of Texas Southwestern Medical Center, Dallas, TX, United States.