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

Tiziano Bernasocchi, Geniver El Tekle, Marco Bolis, Azzurra Mutti, Arianna Vallerga, Laura P. Brandt, Filippo Spriano, Tanya Svinkina, Marita Zoma, Valentina Ceserani, Anna Rinaldi, Hana Janouskova, Daniela Bossi, Manuela Cavalli, Simone Mosole, Roger Geiger, Ze Dong, Cai-Guang Yang, Domenico Albino, Andrea Rinaldi, Peter Schraml, Simon Linder, Giuseppina M. Carbone, Andrea Alimonti, Francesco Bertoni, Holger Moch, Steven A. Carr, Wilbert Zwart, Marianna Kruithof- de Julio, Mark A. Rubin, Namrata D. Udeshi and Jean-Philippe P. Theurillat ()
Additional contact information
Tiziano Bernasocchi: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Geniver El Tekle: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Marco Bolis: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Azzurra Mutti: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Arianna Vallerga: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Laura P. Brandt: University of Bern
Filippo Spriano: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Tanya Svinkina: The Broad Institute of MIT & Harvard
Marita Zoma: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Valentina Ceserani: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Anna Rinaldi: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Hana Janouskova: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Daniela Bossi: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Manuela Cavalli: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Simone Mosole: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Roger Geiger: Institute for Research in Biomedicine
Ze Dong: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Cai-Guang Yang: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Domenico Albino: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Andrea Rinaldi: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Peter Schraml: University Hospital Zurich
Simon Linder: The Netherlands Cancer Institute, Oncode Institute
Giuseppina M. Carbone: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Andrea Alimonti: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Francesco Bertoni: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana
Holger Moch: University Hospital Zurich
Steven A. Carr: The Broad Institute of MIT & Harvard
Wilbert Zwart: The Netherlands Cancer Institute, Oncode Institute
Marianna Kruithof- de Julio: University of Bern
Mark A. Rubin: University of Bern
Namrata D. Udeshi: The Broad Institute of MIT & Harvard
Jean-Philippe P. Theurillat: Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20820-x

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