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  3. Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.
 

Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer.

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BORIS DOI
10.48350/159672
Date of Publication
February 2, 2021
Publication Type
Article
Division/Institute

Department for BioMed...

Department for BioMed...

Universitätsklinik fü...

Author
Bernasocchi, Tiziano
El Tekle, Geniver
Bolis, Marco
Mutti, Azzurra
Vallerga, Arianna
Brandt, Laura Patricia
Department for BioMedical Research (DBMR)
Spriano, Filippo
Svinkina, Tanya
Zoma, Marita
Ceserani, Valentina
Rinaldi, Anna
Janouskova, Hana
Bossi, Daniela
Cavalli, Manuela
Mosole, Simone
Geiger, Roger
Dong, Ze
Yang, Cai-Guang
Albino, Domenico
Rinaldi, Andrea
Schraml, Peter
Linder, Simon
Carbone, Giuseppina M
Alimonti, Andrea
Bertoni, Francesco
Moch, Holger
Carr, Steven A
Zwart, Wilbert
Kruithof-de Julio, Marianna
Universitätsklinik für Urologie
Department for BioMedical Research, Forschungsgruppe Urologie
Rubin, Mark Andrew
Department for BioMedical Research, Forschungsgruppe Präzisionsonkologie
Udeshi, Namrata D
Theurillat, Jean-Philippe P
Subject(s)

600 - Technology::610...

Series
Nature communications
ISSN or ISBN (if monograph)
2041-1723
Publisher
Nature Publishing Group
Language
English
Publisher DOI
10.1038/s41467-020-20820-x
PubMed ID
33531470
Description
Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.
Handle
https://boris-portal.unibe.ch/handle/20.500.12422/45809
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Kruit_Dual_functions_of_SPOP_and_ERG_dictate_androgen_therapy_responses_in_prostate_cancer.pdfAdobe PDF4.54 MBAttribution (CC BY 4.0)publishedOpen
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