Cellular prion protein accelerates colorectal cancer metastasis via the Fyn-SP1-SATB1 axis.

The cellular prion protein (PrPc) is a glycoprotein anchored by glycosylphosphatidylinositol to the cell surface and is abundantly expressed in various tissues. The putative roles of PrPc are thought to be related to cell signaling, survival, and differentiation and cancer progression. In this study, we demonstrated that the expression of PrPc correlates with a more aggressive and histologically unfavorable disease in colorectal carcinomas. Moreover, we found that PrPc mediates the process of epithelial-mesenchymal transition and, thereby, promotes CRC metastasis. Transcriptome profiling of PrPc-depleted cells revealed downregulation of the special AT-rich sequence-binding protein-1 (SATB1). PrPc is demonstrated to be involved in regulating SATB1 expression via the Fyn-SP1 pathway. Since SATB1 has been previously proposed as a key protein that controls tumor development and progression, knockdown of PrPc resulted in a reduced metastatic capacity in CRC cells, as well as a reduction in distant metastases in vivo. In conclusion, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of CRC metastasis. Targeting PrPc will, therefore, be a promising strategy to overcome the metastatic advantage in colorectal tumors.