Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer

Authors

Zhuangzhuang Zhang, University of KentuckyFollow
Lijun Cheng, The Ohio State University
Qiongsi Zhang, University of Kentucky
Yifan Kong, University of KentuckyFollow
Daheng He, University of KentuckyFollow
Kunyu Li, University of Kentucky
Matthew Rea, University of KentuckyFollow
Jianlin Wang, University of KentuckyFollow
Ruixin Wang, University of KentuckyFollow
Jinghui Liu, University of KentuckyFollow
Zhiguo Li, University of KentuckyFollow
Chongli Yuan, Purdue University
Enze Liu, The Ohio State University
Yvonne N. Fondufe-Mittendorf, University of KentuckyFollow
Lang Li, The Ohio State University
Tao Han, The Ohio State University
Chi Wang, University of KentuckyFollow
Xiaoqi Liu, University of KentuckyFollow

Abstract

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.

Document Type

Article

Publication Date

5-29-2021

Notes/Citation Information

Published in Advanced Science, v. 8, issue 13, 2101458.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Digital Object Identifier (DOI)

https://doi.org/10.1002/advs.202101458

Funding Information

This work was funded by NIH R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X.L.). This research was also supported by the University of Kentucky Markey Cancer Center (P30CA177558). The authors deeply appreciate the critical reading of this manuscript by Eleanor Erikson.

Repository Citation

Zhang, Zhuangzhuang; Cheng, Lijun; Zhang, Qiongsi; Kong, Yifan; He, Daheng; Li, Kunyu; Rea, Matthew; Wang, Jianlin; Wang, Ruixin; Liu, Jinghui; Li, Zhiguo; Yuan, Chongli; Liu, Enze; Fondufe-Mittendorf, Yvonne N.; Li, Lang; Han, Tao; Wang, Chi; and Liu, Xiaoqi, "Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer" (2021). Toxicology and Cancer Biology Faculty Publications. 102.
https://uknowledge.uky.edu/toxicology_facpub/102