Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer

• Published in: Advanced science Vol. 8; no. 13; pp. e2101458 - n/a
• Main 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
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-07-2021; John Wiley and Sons Inc; Wiley
• Subjects: Androgens; Animals; Apoptosis; Autophagy; Biology; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; cell death; Correlation analysis; crosstalk; Disease Models, Animal; DNA methylation; DNA Methyltransferase 3A - genetics; DNA Methyltransferase 3A - metabolism; DNMT3a; Gene expression; Humans; Kinases; Male; Mice; PCa; phosphorylation; Plk1, prostate cancer; Polo-Like Kinase 1; Prostate cancer; Prostatic Neoplasms - genetics; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Signal Transduction; autophagy; cell death; crosstalk; Plk1, prostate cancer; DNMT3a; phosphorylation; PCa
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202101458

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.
A unique approach, XDeath is developed to identify novel targets for advanced prostate cancer (PCa). While Polo‐like kinase 1 (Plk1) phosphorylation of DNA methyltransferase 3A (DNMT3a) leads to its degradation in mitosis, DNMT3a represses Plk1 transcription to inhibit autophagy in interphase. This negative feedback loop provides the rationale for a combination therapy to treat advanced PCa.