Open AccessCo‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer
Author(s) -
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,
FondufeMittendorf Yvonne N.,
Li Lang,
Han Tao,
Wang Chi,
Liu Xiaoqi
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202101458
Subject(s) - plk1 , crosstalk , cancer research , autophagy , prostate cancer , mitosis , kinase , biology , methyltransferase , microbiology and biotechnology , chemistry , cell cycle , cancer , gene , apoptosis , methylation , biochemistry , genetics , physics , optics
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.