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

Nature communications (2021-02-04)
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, Jean-Philippe P Theurillat

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.

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Cycloheximide solution, Ready-Made Solution, microbial, 100 mg/mL in DMSO, Suitable for cell culture
MG-132, Ready Made Solution, ≥90% (HPLC)
Corning® Transwell® polycarbonate membrane cell culture inserts, 6.5 mm Transwell with 8.0 μm pore polycarbonate membrane insert, TC-treated, w/lid, sterile, 48/cs
Anti-HA antibody, Mouse monoclonal, clone HA-7, purified from hybridoma cell culture