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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
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Resumo(s)
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.
Descrição
Funding Information: This research was funded by the International Centre for Genetic Engineering and Biotechnology (ICGEB). A.V. was funded by The South African National Research Foundation (NRF) Scarce Skills Doctoral scholarship and ICGEB fellowship; J.D.P. was funded by ICGEB Arturo Falaschi post-doctoral fellowship, and The South African National Research Foundation (NRF) Support for Rated and Unrated Researchers (Grant number SRUG2205067513); M.M. was funded by the ICGEB; N.C.S. was funded by University of Sharjah Targeted grant number 2301101775; T.A.L. was funded by NIH 1R21 CA187843–01; L.F.Z. was funded by the ICGEB. Publisher Copyright: © 2023 by the authors.
Palavras-chave
DCUN1D1 E3 ligase neddylation prostate cancer Wnt/β-catenin pathway General Biochemistry,Genetics and Molecular Biology SDG 3 - Good Health and Well-being