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

Lorenzoni, Marco; De Felice, Dario; Beccaceci, Giulia; Di Donato, Giorgia; Foletto, Veronica; Genovesi, Sacha; Bertossi, Arianna; Cambuli, Francesco; Lorenzin, Francesca; Savino, Aurora; Avalle, Lidia; Cimadamore, Alessia; Montironi, Rodolfo; Weber, Veronica; Carbone, Francesco Giuseppe; Barbareschi, Mattia; Demichelis, Francesca; Romanel, Alessandro; Poli, Valeria; Del Sal, Giannino; ... (2022). ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation. Cancer letters, 534, p. 215612. Elsevier 10.1016/j.canlet.2022.215612

[img]
Preview
Text
1-s2.0-S0304383522000878-main.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial (CC-BY-NC).

Download (46MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

Kruithof-de Julio, Marianna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0304-3835

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

09 Mar 2022 10:51

Last Modified:

25 Mar 2022 00:14

Publisher DOI:

10.1016/j.canlet.2022.215612

PubMed ID:

35259458

Uncontrolled Keywords:

ERG Egf Nkx3.1 Organoids Prostate Wnt

BORIS DOI:

10.48350/166889

URI:

https://boris.unibe.ch/id/eprint/166889

Actions (login required)

Edit item Edit item
Provide Feedback