ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation.

Autor: Lorenzoni M; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., De Felice D; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Beccaceci G; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Di Donato G; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Foletto V; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Genovesi S; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Bertossi A; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Cambuli F; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Lorenzin F; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Savino A; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Avalle L; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Cimadamore A; Pathological Anatomy, School of Medicine, United Hospitals, Polytechnic University of the Marche Region, Ancona, Italy., Montironi R; Molecular Medicine and Cell Therapy Foundation, Polytechnic University of the Marche Region, Via Tronto, 10, Ancona, Italy., Weber V; Unit of Surgical Pathology, Santa Chiara Hospital, Trento, Italy., Carbone FG; Unit of Surgical Pathology, Santa Chiara Hospital, Trento, Italy., Barbareschi M; Unit of Surgical Pathology, Santa Chiara Hospital, Trento, Italy., Demichelis F; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Romanel A; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy., Poli V; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Del Sal G; University of Trieste Department Life Sciences, ICGEB-Area Science Park Trieste, IFOM, Milan, Italy., Julio MK; Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland; Translational Organoid Resource CORE, Department for BioMedical Research, University of Bern, Bern, Switzerland; Bern Center for Precision Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland; Department of Urology, Inselspital, University Hospital of Bern, Bern, Switzerland., Gaspari M; Research Centre for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy. Electronic address: gaspari@unicz.it., Alaimo A; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy. Electronic address: alessandro.alaimo@unitn.it., Lunardi A; Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy. Electronic address: andrea.lunardi@unitn.it.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2022 May 28; Vol. 534, pp. 215612. Date of Electronic Publication: 2022 Mar 05.
DOI: 10.1016/j.canlet.2022.215612
Abstrakt: 21q22.2-3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rearrangement results in the androgen-dependent de novo expression of ETS-related gene (ERG) in prostate cancer cells, a condition promoting tumor progression to advanced stages of the disease. Interestingly, ERG expression characterizes 5-30% of tumor precursor lesions - High Grade Prostatic Intraepithelial Neoplasia (HGPIN) - where its role remains unclear. Here, by combining organoids technology with Click-chemistry coupled Mass Spectrometry, we demonstrate a prominent role of ERG in remodeling the protein secretome of prostate progenitors. Functionally, by lowering autocrine Wnt-4 signaling, ERG represses canonical Wnt pathway in prostate progenitors, and, in turn, promotes the accumulation of DNA double strand breaks via Gsk3β-dependent degradation of the tumor suppressor Nkx3.1. On the other hand, by shaping extracellular paracrine signals, ERG strengthens the pro-oxidative transcriptional signature of inflammatory macrophages, which we demonstrate to infiltrate pre-malignant ERG positive prostate lesions. These findings highlight previously unrecognized functions of ERG in undermining adult prostate progenitor niche through cell autonomous and non-autonomous mechanisms. Overall, by supporting the survival and proliferation of prostate progenitors in the absence of growth stimuli and promoting the accumulation of DNA damage through destabilization of Nkx3.1, ERG could orchestrate the prelude to neoplastic transformation.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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