Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG

Elizabeth V. Wasmuth, Elizabeth A. Hoover, Albert Antar, Sebastian Klinge, Yu Chen, Charles L. Sawyers

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven by oncogenic ETS fusion genes. The molecular basis for this change has remained elusive. Using purified proteins, we report a minimal cell-free system that demonstrates interdomain cooperativity between the ligand (LBD) and DNA binding domains (DBD) of AR, and its autoinhibition by the N terminus of AR. Furthermore, we identify ERG as a cofactor that activates AR's ability to bind DNA in both high and lower affinity contexts through direct interaction within a newly identified AR-interacting motif (AIM) in the ETS domain, independent of ERG's own DNA binding ability. Finally, we present evidence that this interaction is conserved among ETS factors whose expression is altered in prostate cancer. Our work highlights, at a biochemical level, how tumor-initiating ETS trans-locations result in reprogramming of the AR cistrome.

Original languageEnglish (US)
Pages (from-to)8584-8592
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number15
DOIs
StatePublished - Apr 14 2020
Externally publishedYes

Keywords

  • Antiandrogen
  • Cistrome
  • Prostate cancer

ASJC Scopus subject areas

  • General

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