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.
Highlights
The histological evaluation of PCa is expressed in terms of Prostate cancer (PCa) is the most commonly diagnosed solid organ malignancy in men in the United States and remains the second leading cause of cancer death in this population.[1]
Upon systematic analysis of the crosstalk mechanisms of cell-death signaling pathways, we found that AR signaling was diminished, whereas polo-like kinase 1 (Plk1) and DNMT3a signaling were activated during PCa progression
Considering that prostate-specific antigen (PSA) is a clinical biomarker for PCa screening, we examined pattern space exhibition of the variations of gene expression accompanied with AR or PSA
Summary
The histological evaluation of PCa is expressed in terms of Prostate cancer (PCa) is the most commonly diagnosed solid organ malignancy in men in the United States and remains the second leading cause of cancer death in this population.[1]. Analysis of PCa-related dynamic bio-molecular interaction networks will improve our understanding of the complexity of the underlying molecular mechanisms during disease progression.[7] systems biology approaches such as network-based methods have been utilized to dissect the crosstalk mechanisms of signaling pathways in PCa.[8] By integrating multiple expression datasets and protein interaction networks, one can identify functionally related gene modules within a gene community. Quantification of crosstalk revealed a synergistic relationship of these two proteins, suggesting that they could be potential co-targets for the treatment of advanced PCa. Mechanistically, we demonstrated that Plk phosphorylation of DNMT3a resulted in its degradation during mitosis and that DNMT3a-associated inhibition of Plk transcription caused repression of autophagy in interphase. This supports the idea that a combination of Plk inhibition and the DNMT3a inhibitor 5-Aza-2’-deoxycytidine (5-Aza) will offer a new effective approach for PCa treatment
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