Chapter 6: General Discussion, Conclusion and Future Work
6.3 Future Work
Western blot analysis was used to validate and explore the mechanism of action of DCUN1D1 in PCa.
The specificity of this mechanism could be strengthened by determining whether re-introduction of DCUN1D1 by transfection into DU145 DCUN1D1 knockdown cells reverses the observed effects in neddylation, ubiquitination and the WNT/β-catenin pathway. However, immunoprecipitation analysis of the changes in binding dynamics upon dysregulation of DCUN1D1 expression would also be important to determining the extent of functional impact on the observed pathways. Additionally, the functional neddylation assay could be performed to test the ability of thioester linked UBC12 enzyme to mediate NEDD8 transfer in DU145 relative to DU145 DCUN1D1 knockdown PCa cells.
Furthermore, investigation of the ubiquitin E3 complex composition responsible for the degradation of β-catenin would be critical to understanding in what way the disruption in DCUN1D1 has dysregulated the WNT/β-catenin pathway. We observed decreased neddylation of cullin 1 which is a known scaffolding molecule in the SKP1/CUL1/β-TrCP ubiquitin complex that has been demonstrated to mediate β-catenin degradation in the absence of stimulation of the WNT pathway. However, Tripathi et al 2007, demonstrated that cullin 4B negatively regulated β-catenin, therefore, it may be possible that other members of the cullin family of proteins regulate β-catenin in an overlapping manner (Tripathi, Kota and Srinivas, 2007). Meaning that cullin 2, which did not display a decrease in neddylation in this study could be functioning as a scaffolding molecule in a CRL permutation that facilitates the proteasomal degradation of β-catenin. Therefore, it would be interesting to test whether this mechanism was at play in the dysregulation of the WNT/β-catenin pathway following knockdown of DCUN1D1 in PCa. Additionally, it is established that degradation of β-catenin prevents its entry into the nucleus and the co-transcription of WNT target genes. We observed that transcription and regulation of transcription were dysregulated following the analysis of DCUN1D1 pulldown products. Therefore, it would be interesting to determine the impact of the DCUN1D1- associated dysregulation of the WNT/β-catenin pathway by probing the protein-DNA interactions altered using the chromatin-immunoprecipitation assay. It would be interesting to determine if this mechanism is at play in the WNT/β-catenin pathway as DCUN1D1 has been shown to regulate the Hedgehog signalling pathway by binding to the promoter of Gli1 (Sarkaria et al., 2006). Furthermore, the chromatin-immunoprecipitation assay could provide some insights into the nature of the relationship between DCUN1D1 and the histone molecules also identified following IPMS.
Additional exploration of the potential inhibitors of DCUN1D1 would also be interestingly, particularly, in understanding how the inhibition of DCUN1D1 by these compounds leads to blockage of PCa growth. Initially, through screening of the new list of DCUN1D1 signature connected drugs for specificity for DCUN1D1 through exploration of their impact in the presence and absence of DCUN1D1.
Particularly, in terms of podophyllotoxin and thapsigargin which have been found using a transcriptomics and proteomics approach. Further analysis could include in silico docking experiments and investigation of their effect on DCUN1D1-mediated neddylation using the functional neddylation assay against the panel of cullin proteins. It would also be interesting to explore drugs such as palmitoylethanolamide which is an anti-inflammatory agent that targets the PPAR signalling pathway and regulates lipid metabolism. The exploration of the phosphorylation sights of DCUN1D1 that play a role in its activity and perhaps identification of the kinase responsible for this activity would also be interesting. This would advance the understanding of DCUN1D1 activity and potentially identify another approach to targeting DCUN1D1 in PCa treatment.
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