Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-07-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202101458 |
| _version_ | 1819027686136217600 |
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| author | Zhuangzhuang Zhang Lijun Cheng Qiongsi Zhang Yifan Kong Daheng He Kunyu Li Matthew Rea Jianling Wang Ruixin Wang Jinghui Liu Zhiguo Li Chongli Yuan Enze Liu Yvonne N. Fondufe‐Mittendorf Lang Li Tao Han Chi Wang Xiaoqi Liu |
| author_facet | Zhuangzhuang Zhang Lijun Cheng Qiongsi Zhang Yifan Kong Daheng He Kunyu Li Matthew Rea Jianling Wang Ruixin Wang Jinghui Liu Zhiguo Li Chongli Yuan Enze Liu Yvonne N. Fondufe‐Mittendorf Lang Li Tao Han Chi Wang Xiaoqi Liu |
| author_sort | Zhuangzhuang Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T05:46:25Z |
| format | Article |
| id | doaj.art-181714f889ad4418af4847b00328ef31 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-21T05:46:25Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-181714f889ad4418af4847b00328ef312022-12-21T19:14:06ZengWileyAdvanced Science2198-38442021-07-01813n/an/a10.1002/advs.202101458Co‐Targeting Plk1 and DNMT3a in Advanced Prostate CancerZhuangzhuang Zhang0Lijun Cheng1Qiongsi Zhang2Yifan Kong3Daheng He4Kunyu Li5Matthew Rea6Jianling Wang7Ruixin Wang8Jinghui Liu9Zhiguo Li10Chongli Yuan11Enze Liu12Yvonne N. Fondufe‐Mittendorf13Lang Li14Tao Han15Chi Wang16Xiaoqi Liu17Department of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Biomedical Informatics The Ohio State University Columbus OH 43210 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USAMarkey Cancer Center University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Molecular and Cellular Biochemistry University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USASchool of Chemical Engineering Purdue University West Lafayette IN 47907 USADepartment of Biomedical Informatics The Ohio State University Columbus OH 43210 USADepartment of Molecular and Cellular Biochemistry University of Kentucky Lexington KY 40536 USADepartment of Biomedical Informatics The Ohio State University Columbus OH 43210 USADepartment of Biomedical Informatics The Ohio State University Columbus OH 43210 USAMarkey Cancer Center University of Kentucky Lexington KY 40536 USADepartment of Toxicology and Cancer Biology University of Kentucky Lexington KY 40536 USAAbstract 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.https://doi.org/10.1002/advs.202101458autophagycell deathcrosstalkDNMT3aPCaphosphorylation |
| spellingShingle | Zhuangzhuang Zhang Lijun Cheng Qiongsi Zhang Yifan Kong Daheng He Kunyu Li Matthew Rea Jianling Wang Ruixin Wang Jinghui Liu Zhiguo Li Chongli Yuan Enze Liu Yvonne N. Fondufe‐Mittendorf Lang Li Tao Han Chi Wang Xiaoqi Liu Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer Advanced Science autophagy cell death crosstalk DNMT3a PCa phosphorylation |
| title | Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer |
| title_full | Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer |
| title_fullStr | Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer |
| title_full_unstemmed | Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer |
| title_short | Co‐Targeting Plk1 and DNMT3a in Advanced Prostate Cancer |
| title_sort | co targeting plk1 and dnmt3a in advanced prostate cancer |
| topic | autophagy cell death crosstalk DNMT3a PCa phosphorylation |
| url | https://doi.org/10.1002/advs.202101458 |
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