Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis

Gabriel J Sandoval; John L Pulice; Hubert Pakula; Monica Schenone; David Y Takeda; Marius Pop; Gaylor Boulay; Kaylyn E Williamson; Matthew J McBride; Joshua Pan; Roodolph St Pierre; Emily Hartman; Levi A Garraway; Steven A Carr; Miguel N Rivera; Zhe Li; Lucienne Ronco; William C Hahn; Cigall Kadoch

doi:10.1016/j.molcel.2018.06.040

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis

Mol Cell. 2018 Aug 16;71(4):554-566.e7. doi: 10.1016/j.molcel.2018.06.040. Epub 2018 Aug 2.

Authors

Gabriel J Sandoval¹, John L Pulice², Hubert Pakula³, Monica Schenone⁴, David Y Takeda⁵, Marius Pop⁵, Gaylor Boulay⁶, Kaylyn E Williamson², Matthew J McBride⁷, Joshua Pan², Roodolph St Pierre⁸, Emily Hartman⁴, Levi A Garraway⁵, Steven A Carr⁴, Miguel N Rivera⁶, Zhe Li³, Lucienne Ronco⁴, William C Hahn⁹, Cigall Kadoch¹⁰

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Pathology and MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Chemical Biology Program, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Chemical Biology Program, Harvard Medical School, Boston, MA, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: william_hahn@dfci.harvard.edu.
¹⁰ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: cigall_kadoch@dfci.harvard.edu.

Abstract

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

Keywords: ATP-dependent chromatin remodeling; ETS transcription factors; SWI/SNF (BAF) complexes; TMPRSS2-ERG; chromatin; epigenetics; prostate cancer; transcription factor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenovirus E1A Proteins / genetics
Adenovirus E1A Proteins / metabolism
Animals
Binding Sites
Carcinogenesis / genetics*
Cell Line, Tumor
Cell Proliferation
Chromatin / chemistry
Chromatin / metabolism
Chromatin Assembly and Disassembly
DNA / genetics
DNA / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Regulation, Neoplastic*
HEK293 Cells
Humans
Male
Mice, Transgenic
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Organoids / metabolism
Organoids / pathology
Prostate / metabolism
Prostate / pathology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Protein Binding
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-ets
Serine Endopeptidases / genetics*
Serine Endopeptidases / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptional Regulator ERG / genetics
Transcriptional Regulator ERG / metabolism

Substances

Adenovirus E1A Proteins
BANF1 protein, human
Chromatin
DNA-Binding Proteins
ERG protein, human
ETV1 protein, human
ETV4 protein, human
ETV5 protein, human
Nuclear Proteins
Oncogene Proteins, Fusion
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-ets
Transcription Factors
Transcriptional Regulator ERG
DNA
Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding