A novel Cullin4-based ubiquitin E3 ligase regulates PML proteasomal degradation to promote lung cancer progression
| Autor: | Jocelyn Fang-Yi Chen, 程方怡 |
|---|---|
| Rok vydání: | 2015 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 103 The PML (promyelocytic leukemia) protein plays pleiotropic roles in tumor suppression and its downregulation has been observed in multiple types of human cancers. While previous studies revealed the contribution of ubiquitin-proteasome system to PML degradation in tumors, the precise mechanism for PML ubiquitination has not been completely understood. Here, we discovered that a Cullin4-based complex containing WDR4 substrate adaptor and two common subunits DDB1 and Roc1 as a novel PML ubiquitin ligase. WDR4 potentiated PML ubiquitination and proteasomal degradation and decreased PML half-life through a mechanism depending on its interaction with DDB1. Since clinical evidence implicated a hyperactivation of WDR4/PML axis in lung cancer, we sought to investigate the biological significance of this pathway in lung cancer progression. To this end, lung cancer cell line A549 transfected with WDR4 or siPML was subjected to microarray analysis to identify genes that were coregulated under both treatments. CD73, uPAR, and SAA2 were identified and verified as target genes of WDR4/PML axis. Importantly, they are all reported to potentiate tumor progression by regulating tumor microenvironment, thereby potentiating tumor proliferation, migration, invasion, and metastasis. Consistent with the discovery of these target genes, we showed that WDR4/PML axis simulated lung cancer proliferation, migration, and invasion, which is likely mediated by upregulation of several tumor-promoting factors and ECM remodeling genes. Together, we identified a novel PML ubiquitin ligase and demonstrated the functions of this PML ubiquitination pathway in lung cancer progression using cell-based analyses. In the future, we will test the role of this pathway in lung cancer progression by animal models. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|