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.

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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.

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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.

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