The Effects of circPKN2 on Ferroptosis in Bladder Cancer - Expert Commentary
The investigators collected paired tumors and adjacent samples from 46 patients who were undergoing radical resection. The expression of circPKN2 was found to be significantly downregulated in BC patient samples and cell lines. Higher circPKN2 expression was associated with longer overall survival (OS, p = 0.028) and disease-free survival (DFS, p = 0.025). Furthermore, circPKN2 was significantly associated with tumor size, N stage, and muscle invasion (p < 0.05). In BC cell lines, the overexpression of circPKN2 led to significant reductions in proliferation, migration, and invasion (p < 0.001). circPKN2 levels were associated with expression levels of proteins involved in cell proliferation and epithelial-to-mesenchymal (EMT) transition. Interestingly, circPKN2 was found to promote ferroptosis in BC cells. Further dissection of pathways regulated by circPKN2 identified SCD1 as a potential binding protein. Indeed, circPKN2 and SCD1 were found to colocalize in BC cells. The expression levels of circPKN2 and SCD1 were found to be inversely correlated in BC tissue samples. Subsequent follow-up experiments revealed that circPKN2 promoted protein degradation of SCD1 through the ubiquitin-proteasome pathway by recruiting the E3 ubiquitin ligase STUB1. Furthermore, high levels of SCD1 were associated with poorer prognosis in patients (p = 0.018). circPKN2 was also found to regulate WNT pathway signaling. The investigators subsequently validated these findings in mice showing larger tumor volumes in the circPKN2 knockdown compared to controls (p < 0.001). Interestingly, Mice with circPKN2 knockdown exhibited a significant increase in lung metastasis relative to controls (p < 0.01).
The findings from this study highlight circPKN2 as a potential target. Future studies should be conducted on potential therapies that can increase the activity and expression of circPKN2 to rescue its beneficial effects on cellular pathways and cellular phenotypes.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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