ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3ß dependent Nkx3.1 degradation.
Cancer Lett
; 534: 215612, 2022 05 28.
Article
in En
| MEDLINE
| ID: mdl-35259458
ABSTRACT
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 Gsk3ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prostate
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Prostatic Neoplasms
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Transcription Factors
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Homeodomain Proteins
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Glycogen Synthase Kinase 3 beta
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Transcriptional Regulator ERG
Limits:
Animals
Language:
En
Journal:
Cancer Lett
Year:
2022
Document type:
Article
Affiliation country:
Italy