Her4 promotes cancer metabolic reprogramming via the c-Myc-dependent signaling axis.

Despite the growing recognition of metabolic reprogramming as an important hallmark of cancer in the past few years, the molecular mechanisms underlying metabolic alterations during tumorigenesis remain unclear. In this study, we identified a critical role of Her4 in rewiring cancer metabolism toward 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-MycS62 phosphorylation and GSK3β-mediated decrease in c-MycT58 phosphorylation, both of which decreased c-Myc degradation. Furthermore, Her4 was found to increase glucose uptake and tumor growth in an osteosarcoma xenograft model. Overall, these findings provide a better understanding of the involvement of Her4 in tumorigenesis and document its potential role in metabolic reprogramming for the first time. We believe that our study might lead to promising opportunities for targeted metabolic therapy for cancer.