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

被引：8

作者：

Lorenzoni, Marco ^{[1
,12
]}

De Felice, Dario ^{[1
]}

Beccaceci, Giulia ^{[1
]}

Di Donato, Giorgia ^{[1
]}

Foletto, Veronica ^{[1
]}

Genovesi, Sacha ^{[1
]}

Bertossi, Arianna ^{[1
]}

Cambuli, Francesco ^{[1
,13
]}

Lorenzin, Francesca ^{[1
]}

Savino, Aurora ^{[2
]}

Avalle, Lidia ^{[2
]}

Cimadamore, Alessia ^{[3
]}

Montironi, Rodolfo ^{[4
]}

Weber, Veronica ^{[5
]}

Carbone, Francesco Giuseppe ^{[5
]}

Barbareschi, Mattia ^{[5
]}

Demichelis, Francesca ^{[1
]}

Romanel, Alessandro ^{[1
]}

Poli, Valeria ^{[2
]}

Del Sal, Giannino ^{[6
]}

Kruithof-de Julio, Marianna ^{[7
,8
,9
,10
]}

Gaspari, Marco ^{[11
]}

Alaimo, Alessandro ^{[1
]}

Lunardi, Andrea ^{[1
]}

机构：

[1] Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Trento, Italy

[2] Univ Torino, Dept Mol Biotechnol & Hlth Sci, Turin, Italy

[3] Polytech Univ Marche Reg, United Hosp, Sch Med, Pathol Anat, Ancona, Italy

[4] Polytech Univ Marche Reg, Mol Med & Cell Therapy Fdn, Via Tronto 10, Ancona, Italy

[5] Santa Chiara Hosp, Unit Surg Pathol, Trento, Italy

[6] Univ Trieste, IFOM, Dept Life Sci, ICGEB Area Sci Pk Trieste, Milan, Italy

[7] Univ Bern, Dept BioMed Res DBMR, Urol Res Lab, Bern, Switzerland

[8] Univ Bern, Dept BioMed Res, Translat Organoid Resource CORE, Bern, Switzerland

[9] Univ Hosp Bern, Bern Ctr Precis Med, Inselspital, Bern, Switzerland

[10] Univ Hosp Bern, Dept Urol, Inselspital, Bern, Switzerland

[11] Magna Graecia Univ Catanzaro, Res Ctr Adv Biochem & Mol Biol, Dept Expt & Clin Med, Catanzaro, Italy

[12] IRCCS Osped San Raffaele, Cellular Immunol Unit, Milan, Italy

[13] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, Sloan Kettering Inst, 1275 York Ave, New York, NY 10021 USA

来源：

CANCER LETTERS | 2022年 / 534卷

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

Prostate; Organoids; ERG; Wnt; Nkx3; 1; Egf; ANDROGEN RECEPTOR; INTRAEPITHELIAL NEOPLASIA; CANCER GROWTH; STEM-CELL; TMPRSS2-ERG; EXPRESSION; FUSION; PROMOTES; ENRICHMENT; PROTEIN;

D O I：

10.1016/j.canlet.2022.215612

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

21q22.2-3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rear-rangement 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 Intra-epithelial 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 Gsk3 beta-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.

引用

页数：17