Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation.,This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes.,However, to date no study has reported miRNA-mediated regulation of ferroptosis.,Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells.,Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation.,Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis.,Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo.,Collectively, these data indicate that miR-137 plays a novel and indispensable role in ferroptosis by inhibiting glutaminolysis and suggest a potential therapeutic approach for melanoma.
The molecular mechanisms mediating CYLD tumor suppressor function appear to be manifold.,Here, we demonstrated that, in contrast to the increased levels of pJNK, CYLD was decreased in a majority of melanoma cell lines and tissues examined.,Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo.,In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection.,At the molecular level, CYLD decreased β1-integrin and inhibited pJNK induction by TNFα or cell-attachment to collagen IV.,Moreover, CYLD induced an array of other molecular changes associated with modulation of the ‘malignant’ phenotype, including a decreased expression of cyclin D1, N-cadherin and nuclear Bcl3, and an increased expression of p53 and E-cadherin.,Most interestingly, co-expression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo.,Our findings demonstrate that JNK/AP-1 signaling pathway underlies the melanoma growth and metastasis that is associated with CYLD loss-of-function.,Thus, restoration of CYLD and inhibition of JNK and β1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.