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Nat Commun DOI:10.1038/s41467-020-20820-x

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

Publication TypeJournal Article
Year of Publication2021
AuthorsBernasocchi, T, Tekle, GEl, Bolis, M, Mutti, A, Vallerga, A, Brandt, LP, Spriano, F, Svinkina, T, Zoma, M, Ceserani, V, Rinaldi, A, Janouskova, H, Bossi, D, Cavalli, M, Mosole, S, Geiger, R, Dong, Z, Yang, C-G, Albino, D, Rinaldi, A, Schraml, P, Linder, S, Carbone, GM, Alimonti, A, Bertoni, F, Moch, H, Carr, SA, Zwart, W, de Julio, MKruithof-, Rubin, MA, Udeshi, ND, Theurillat, J-PP
JournalNat Commun
Volume12
Issue1
Pages734
Date Published2021 02 02
ISSN2041-1723
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.

DOI10.1038/s41467-020-20820-x
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33531470?dopt=Abstract

Alternate JournalNat Commun
PubMed ID33531470
Grant ListU24 CA210986 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States