Function And Mechanism Of LncRNA LncRIM In Cellular Iron Metabolism Reprogramming And Breast Cancer Malignancy By Mediating The Hippo Signaling

Cancer cells require metabolic reprogramming to maintain malignant progression.To meet the demands of proliferation,cancer cells require more nutrients and energy,such as glucose,amino acids,and lipids et al.As one of the important trace elements,iron coordinates multiple tissue and physiological homeostasis,and iron metabolism disorders will drive the progression and malignancy of tumor,but the mechanism still needs more investigation.In this study,we found the correlation between the abnormal iron metabolism in tumor and the Hippo signaling pathway through bioinformatics analysis and iron staining of breast cancer tissue.By stimulating cells with FAC and DFO,we screened and identified one lnc RNA Loc729013,which dynamically responded to iron level and in turn regulated cellular iron metabolism,and we renamed it as LncRIM(LncRNA Related to Iron Metabolism).Besides,clinical cohort analysis showed that LncRIM was highly expressed in human breast cancer tissues,and was associated with poor patient survival,suggesting the oncogenic role of LncRIM.Mechanically,LncRIM directly bound to NF2,one protein upstream of the Hippo signaling pathway,and colocalized at cell membrane,which antagonized the association between NF2 and LATS1 and led to YAP activation.Besides,we found that LncRIM-NF2 axis was dependent on the Hippo pathway to drive cellular iron metabolism reprogramming effectively via promoting the expression of DMT1 and TFR1,both transcription targets of YAP,and this regulatory mechanism was largely independent of the IRP/IRE system.Moreover,we also revealed that the Hippo signaling pathway dynamically responded to cellular iron level,and LncRIM-NF2-DMT1/TFR1 axis mediated iron metabolism feedback and in turn hyperactivated YAP,which finally promoted cell proliferation.Further,by constructing subcutaneous and orthotopic tumor transplantation models,we investigated the effect of LncRIM mediated cellular iron metabolism reprogramming on tumor growth in vivo.And we found that overexpressed LncRIM could upregulate cellular iron level and inhibit the Hippo pathway to drive tumor growth,while knocking down DMT1 and TFR1 or injecting DFO into the abdominal cavity both significantly inhibited LncRIM mediated iron metabolism reprogramming,YAP activation and tumor growth.These studies further clarified the importance of iron metabolism in LncRIM mediated tumor growth in vivo.Together,our study provided one new mechanism in which LncRIM-NF2 axis wires up the Hippo signaling pathway to regulate cellular iron reprogramming and in turn activates YAP to promote breast cancer development and malignancy,suggesting the potential use of LncRIM as a biomarker and therapeutic target.