2. Academic Validation
  3. DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3β and WEE1

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

  • Mol Cell. 2020 Sep 17;79(6):1008-1023.e4. doi: 10.1016/j.molcel.2020.07.028.
Zhe Hong 1,  Wei Zhang 2,  Donglin Ding 3,  Zhenlin Huang 3,  Yuqian Yan 3,  William Cao 3,  Yunqian Pan 3,  Xiaonan Hou 4,  Saravut J Weroha 4,  R Jeffrey Karnes 5,  Dejie Wang 3,  Qiang Wu 6,  Denglong Wu 7,  Haojie Huang 8
Affiliations

Affiliations

  • 1 Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
  • 2 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Basic Medical College, Jilin Medical University, Jilin, Jilin 132013, China.
  • 3 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
  • 4 Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 5 Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
  • 6 Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA. Electronic address: [email protected].
  • 7 Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: [email protected].
  • 8 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA. Electronic address: [email protected].
PMID: 32871104 DOI: 10.1016/j.molcel.2020.07.028
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.

Keywords

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

Figures
Products