Ferroptosis induced by DCPS depletion diminishes hepatic metastasis in uveal melanoma

Hepatic metastasis develops in similar to 50% of uveal melanoma (UM) patients with scarcely effective treatment resulting in lethality. The underlying mechanism of liver metastasis remains elusive. Ferroptosis, a cell death form characterized by lipid peroxide, in cancer cells may decrease metastatic colonization. In the present study, we hypothesized that decapping scavenger enzymes (DCPS) impact ferroptosis by regulating mRNA decay during the metastatic colonization of UM cells to liver. We found that inhibition of DCPS by shRNA or RG3039 induced gene transcript alteration and ferroptosis through reducing the mRNA turnover of GLRX. Ferroptosis induced by DCPS inhibition eliminates cancer stem-like cells in UM. Inhibition of DCPS hampered the growth and prolif-eration both in vitro and in vivo. Furthermore, targeting DCPS diminished hepatic metastasis of UM cells. These findings may shed light on the understanding of DCPS-mediated pre-mRNA metabolic pathway in UM by which disseminated cells gain enhanced malignant features to promote hepatic metastasis, providing a rational target for metastatic colonization in UM.

Automated summary

Hepatic metastasis is a common and poorly treated cause of death in uveal melanoma (UM) patients. The mechanism underlying liver metastasis remains unknown. This study suggests that decapping scavenger enzymes (DCPS) impact ferroptosis by regulating mRNA decay during the metastatic colonization of UM cells to liver. Inhibition of DCPS induces gene transcript alteration and ferroptosis by reducing the mRNA turnover of GLRX. Inhibition of DCPS also eliminates cancer stem-like cells in UM and hampers the growth and proliferation of UM cells both in vitro and in vivo. Additionally, targeting DCPS diminishes hepatic metastasis of UM cells, providing a potential target for metastatic colonization in UM.