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

Bernasocchi, Tiziano; El Tekle, Geniver; Bolis, Marco; Mutti, Azzurra; Vallerga, Arianna; Brandt, Laura P.; 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; ... (2021). Dual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer. Nature communications, 12(1), p. 734. Nature Publishing Group 10.1038/s41467-020-20820-x

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
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:

Brandt, Laura Patricia; Kruithof-de Julio, Marianna and Rubin, Mark Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Jeannine Wiemann

Date Deposited:

13 Oct 2021 11:28

Last Modified:

13 Oct 2021 11:28

Publisher DOI:

10.1038/s41467-020-20820-x

PubMed ID:

33531470

BORIS DOI:

10.48350/159672

URI:

https://boris.unibe.ch/id/eprint/159672

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