Title: Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer.

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

Published In Adv Sci (Weinh), (2021 Jul)

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.

PubMed ID: 34051063

MeSH Terms: Animals; Cell Cycle Proteins/genetics*; Cell Cycle Proteins/metabolism*; DNA Methyltransferase 3A/genetics*; DNA Methyltransferase 3A/metabolism*; Disease Models, Animal; Humans; Male; Mice; Polo-Like Kinase 1; Prostatic Neoplasms/genetics*; Protein Serine-Threonine Kinases/genetics*; Protein Serine-Threonine Kinases/metabolism*; Proto-Oncogene Proteins/genetics*; Proto-Oncogene Proteins/metabolism*; Signal Transduction