Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer

Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianling Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 phosphorylation of DNMT3a leads to its degradation in mitosis and that DNMT3a represses Plk1 transcription to inhibit autophagy in interphase, suggesting a negative feedback loop between these two proteins. Finally, a combination of the DNMT inhibitor 5-Aza-2’-deoxycytidine (5-Aza) with inhibition of Plk1 suppresses PCa synergistically.

Original languageEnglish
Article number2101458
JournalAdvanced Science
Issue number13
StatePublished - Jul 7 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.


  • DNMT3a
  • PCa
  • Plk1, prostate cancer
  • autophagy
  • cell death
  • crosstalk
  • phosphorylation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Chemical Engineering
  • General Materials Science
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • General Engineering
  • General Physics and Astronomy


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