Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer

Xin Li, Lajos Gera, Shumin Zhang, Yanhua Chen, Lei Lou, Lauren Marie Wilson, Zhong Ru Xie, Giuseppe Sautto, Degang Liu, Alira Danaher, Kenza Mamouni, Yang Yang, Yuhong Du, Haian Fu, Omer Kucuk, Adeboye O. Osunkoya, Jia Zhou, Daqing Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-Associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.

Original languageEnglish (US)
Pages (from-to)6873-6890
Number of pages18
JournalTheranostics
Volume11
Issue number14
DOIs
StatePublished - 2021
Externally publishedYes

Keywords

  • chemoresistance
  • drug discovery
  • EED inhibitor
  • EZH2 signaling
  • prostate cancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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