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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers, Tumor / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Co-Repressor Proteins / genetics
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Co-Repressor Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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HEK293 Cells
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Humans
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Immunohistochemistry
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Immunoprecipitation
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Male
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Mice
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Mice, Nude
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Mutation / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Protein Binding
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Proteomics
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Receptors, Androgen / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction / physiology
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Transcriptional Regulator ERG / genetics
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Transcriptional Regulator ERG / metabolism*
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Ubiquitin-Protein Ligase Complexes / genetics
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Ubiquitin-Protein Ligase Complexes / metabolism*
Substances
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Biomarkers, Tumor
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Cell Cycle Proteins
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Co-Repressor Proteins
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DNA-Binding Proteins
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ERG protein, mouse
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Nuclear Proteins
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Oncogene Proteins
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Receptors, Androgen
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Repressor Proteins
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SPOP protein, human
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Transcriptional Regulator ERG
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ZMYND11 protein, human
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Zmynd11 protein, mouse
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Spop protein, mouse
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Ubiquitin-Protein Ligase Complexes