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

• DOI: 10.1038/s41467-020-20820-x
• Publication Date: 2021-02-02T13:21:09Z
• Authors: 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. Car...; Andrea Alimonti; Francesco Bertoni; Holger Moch; Steven A. Carr; Wilbert Zwart; Marianna Kruithof...; Mark A. Rubin; Namrata D. Udeshi; Jean-Philippe P. ...
• Keywords: Chromoplexy

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 prostate cancer driver alterations involving the ERG transcription factor and ubiquitin ligase adaptor SPOP synthetic sick. At molecular level, incompatible pathways driven by opposing functions SPOP. upregulates wild type dampen androgen receptor (AR) signaling sustain activity through degradation of bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 repress ERG-function enable oncogenic signaling. This dichotomy regulates response therapeutic interventions AR pathway. While mutant renders cells susceptible deprivation therapies, promotes sensitivity high-dose therapy pharmacological inhibition More generally, these results define distinct class antagonistic drivers blueprint toward their exploitation.