Mechanism For Her4-mediated Cancer Metabolic Reprogramming Via The C-Myc-dependent Signaling Axis Jing Han

Background:Malignant tumor is not only a genetic disease,but also a metabolic disease.Despite the growing recognition of metabolic reprogramming as an important hallmark of cancer in the past few years,the regulation of metabolic reprogramming is not fully understood.Unlike other family members（EGFR and Her2）,which are well-known cancer targets,study focusing on the role of Her4 in cancer is relatively lacking.Our previous study demonstrated that Her4 protected neuroblastoma cells against multiple cellular stresses and induced chemo-resistance.We had also found a positive correlation between high expression of Her4 and poor prognosis in osteosarcoma patients.Moreover,Her4 promoted survival and chemo-resistance of osteosarcoma cells in adverse conditions.Although there has been increasing evidence of the oncogenic effect of Her4 during the past few years,complete understanding of the involvement of Her4 in tumorigenesis is still lacking.In particular,its potential role in cancer metabolic reprogramming remains to be investigated.Obejctive:To explore the potential role of Her4 in the regulation of cancer metabolic reprogramming and its related mechanism.Methods:（1）Western blot was used to detect Her4 expression in different cancer cell lines.（2）To investigate the effect of Her4 on metabolic reprogramming in different types of cancer cell lines through metabolomics analysis,Seahorse stress test,etc.（3）To investigate the potential mechanism of Her4 in the regulation of cancer metabolic reprogramming through western blot,RT-PCR,Co-IP assays,etc.（4）Nude mice xenograft model was used to investigate the effect of Her4 on cancer metabolic reprogramming and further verify its related mechanism in vivo through ¹⁸F-FDG micro PET/CT scan,western blot,etc.Results:It is known that upregulation of Her4 expression in cancers increases tumor-promoting metabolic processes including increased glycolysis,glutaminolysis,mitochondrial biogenesis,and oxidative phosphorylation,which may in part cooperate to promote tumorigenesis.We found that overexpression of Her4 promoted the stabilization of c-Myc through a CIP2A-mediated increase in c-Myc ^S62phosphorylation and GSK3β-mediated decrease in c-Myc ^T58phosphorylation,both of which decreased c-Myc degradation.Furthermore,Her4 was found to activate c-Myc signaling axis and increase glucose uptake and tumor growth in an osteosarcoma xenograft model.Conclusions:Her4 promotes cancer metabolic reprogramming by promoting the stabilization of c-Myc through CIP2A-mediated increase in c-Myc ^S62phosphorylation and GSK3β-mediated decrease in c-Myc ^T58phosphorylation.Our study provides a new perspective and in-depth understanding of the involvement of Her4 in tumorigenesis.We believe that our study might lead to promising opportunities for targeted metabolic therapy for cancer.