Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer.

Autor:	Santasusagna S; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Zhu S; Department of Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota., Jawalagatti V; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Carceles-Cordon M; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Ertel A; Department of Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Garcia-Longarte S; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain., Song WM; Department of Genetics and Genome Sciences, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York., Fujiwara N; Department of Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Li P; Department of Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Mendizabal I; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain., Petrylak DP; Department of Oncology, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut., Kelly WK; Department of Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Reddy EP; Department of Oncological Sciences, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York., Wang L; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Schiewer MJ; Department of Pharmacology, Physio-logy, and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Lujambio A; Department of Oncological Sciences, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York., Karnes J; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Knudsen KE; Department of Pharmacology, Physio-logy, and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Cordon-Cardo C; Department of Pathology. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York., Dong H; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Immunology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Huang H; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Carracedo A; Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.; Traslational prostate cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.; CIBERONC, Madrid, Spain.; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain., Hoshida Y; Department of Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Rodriguez-Bravo V; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota., Domingo-Domenech J; Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 Dec 12; Vol. 13 (12), pp. 2584-2609.
DOI:	10.1158/2159-8290.CD-23-0306
Abstrakt:	Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming 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' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. Significance: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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