MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression

Dallavalle, Cecilia; Albino, Domenico; Civenni, Gianluca; Merulla, Jessica; Ostano, Paola; Mello-Grand, Maurizia; Rossi, Simona; Losa, Marco; D'Ambrosio, Gioacchino; Sessa, Fausto; Thalmann, George; Garcia-Escudero, Ramon; Zitella, Andrea; Chiorino, Giovanna; Catapano, Carlo V; Carbone, Giuseppina M (2016). MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression. Journal of clinical investigation, 126(12), pp. 4585-4602. American Society for Clinical Investigation 10.1172/JCI86505

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Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF-deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Thalmann, George

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Katharina Morgenegg

Date Deposited:

14 Mar 2017 11:12

Last Modified:

16 Mar 2017 03:14

Publisher DOI:

10.1172/JCI86505

PubMed ID:

27820701

BORIS DOI:

10.7892/boris.92727

URI:

https://boris.unibe.ch/id/eprint/92727

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