DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3β and WEE1

Zhe Hong, Wei Zhang, Donglin Ding, Zhenlin Huang, Yuqian Yan, William Cao, Yunqian Pan, Xiaonan Hou, Saravut J. Weroha, R. Jeffrey Karnes, Dejie Wang, Qiang Wu, Denglong Wu, Haojie Huang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3β inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3β signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa.

Original languageEnglish (US)
Pages (from-to)1008-1023.e4
JournalMolecular Cell
Volume79
Issue number6
DOIs
StatePublished - Sep 17 2020

Keywords

  • ERG
  • FBW7
  • GSK3β
  • PTEN
  • WEE1
  • phosphorylation
  • prostate cancer
  • radiotherapy
  • therapy resistance
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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