RNF185 control of COL3A1 expression impacts prostate cancer migration and metastatic potential
RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER associated degradation. Analysis of prostate tumor patient data revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture, upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells that stably express shRNA against RNF185 into B6 mice, resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound healing and cellular movement among the most significantly upregulated pathways in RNF185-depleted prostate cancer cells, compared with control. Gene Set Enrichment Analyses that were performed in both patients harboring low RNF185 expression, and in RNF185-depleted cell lines, confirmed deregulation of genes implicated in EMT. Among those, COL3A1 was identified as the primary mediator of RNF185 ability to impact the migration phenotype. Correspondingly, enhanced migration of RNF185 KD prostate cancer cells was abolished upon COL3A1 inhibition.  Taken together, our results identify RNF185 as gatekeeper of prostate cancer metastasis, in part by its control of COL3A1 transcription. Overall design: Gene expression comparison of  RNF185 KD and control in MPC3 cell line using RNA-seq.