Abstract
Abstract RNF185 is a RING finger domain-containing ubiquitin ligase which is anchored to the ER and resemble RNF5, a ubiquitin ligase implicated in ER associated degradation. In prostate cancer, deregulation of the expression or activity of several ubiquitin ligases has been shown to contribute to disease progression (e.g., Siah2, SPOP, RNF6). Analysis of prostate tumor patient data revealed a negative correlation between RNF185 expression and prostate adenocarcinoma progression and metastasis. Supporting these observations, several prostate cancer cell lines exhibited greater migration and invasion capabilities upon RNF185 depletion, in vitro. Subcutaneous inoculation of mouse prostate cancer MPC3 cells, stably expressing shRNA against RNF185, resulted in larger tumors and more frequent lung metastases in NSG mice. These results suggest that the increased metastatic potential associated with lower RNF185 levels may depend on molecular changes intrinsic to the tumors cells. RNA-sequencing and Ingenuity Pathway Analysis of RNF185-depleted compared to control MPC3 cells identified wound healing and cellular movement among the most significantly upregulated pathways in RNF185-depleted cells. Transcription regulators of Epithelial-Mesenchymal Transition (EMT) Snai2 and Zeb1 were among the most upregulated genes that were predicted to be activated based on the expression of their target genes. Comparison between differentially expressed genes in patients with low RNF185 expression, and RNF185-depleted cell lines (from mouse and human prostate tumors) confirmed deregulation of genes implicated in EMT. Taken together, our results identify RNF185 as gatekeeper of prostate cancer metastasis, via its control of EMT genes implicated in cell motility and metastasis. Citation Format: Benjamin Van Espen, Ladan Fazli, Htoo Z. Oo, Rabi Murad, Martin Gleave, Ze'ev A. Ronai. RNF185 modulates prostate cancer metastatic potential through regulation of epithelial-mesenchymal transition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A023.
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