DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway
Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DC...
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2023-07-01
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| author | Akhona Vava Juliano D. Paccez Yihong Wang Xuesong Gu Manoj K. Bhasin Michael Myers Nelson C. Soares Towia A. Libermann Luiz F. Zerbini |
| author_facet | Akhona Vava Juliano D. Paccez Yihong Wang Xuesong Gu Manoj K. Bhasin Michael Myers Nelson C. Soares Towia A. Libermann Luiz F. Zerbini |
| author_sort | Akhona Vava |
| collection | DOAJ |
| description | Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy. |
| first_indexed | 2024-03-11T00:29:12Z |
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| id | doaj.art-36300f00f80d419a801b52f5097ea6ec |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T00:29:12Z |
| publishDate | 2023-07-01 |
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| series | Cells |
| spelling | doaj.art-36300f00f80d419a801b52f5097ea6ec2023-11-18T22:45:09ZengMDPI AGCells2073-44092023-07-011215197310.3390/cells12151973DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin PathwayAkhona Vava0Juliano D. Paccez1Yihong Wang2Xuesong Gu3Manoj K. Bhasin4Michael Myers5Nelson C. Soares6Towia A. Libermann7Luiz F. Zerbini8Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South AfricaCancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South AfricaDepartment of Pathology and Laboratory Medicine, Warren Alpert School of Medicine, Brown University, Providence, RI 02912, USABIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USADepartment of Pediatrics Bioinformatics, Emory University School of Medicine, Atlanta, GA 30322, USAProtein Networks Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, ItalyDepartment of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 26666, United Arab EmiratesBIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USACancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town 7925, South AfricaDefective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.https://www.mdpi.com/2073-4409/12/15/1973prostate cancerE3 ligaseDCUN1D1neddylationWnt/β-catenin pathway |
| spellingShingle | Akhona Vava Juliano D. Paccez Yihong Wang Xuesong Gu Manoj K. Bhasin Michael Myers Nelson C. Soares Towia A. Libermann Luiz F. Zerbini DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway Cells prostate cancer E3 ligase DCUN1D1 neddylation Wnt/β-catenin pathway |
| title | DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway |
| title_full | DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway |
| title_fullStr | DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway |
| title_full_unstemmed | DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway |
| title_short | DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway |
| title_sort | dcun1d1 is an essential regulator of prostate cancer proliferation and tumour growth that acts through neddylation of cullin 1 3 4a and 5 and deregulation of wnt catenin pathway |
| topic | prostate cancer E3 ligase DCUN1D1 neddylation Wnt/β-catenin pathway |
| url | https://www.mdpi.com/2073-4409/12/15/1973 |
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