The Role of Hexokinase 2 in Breast Cancer Metastasis

One hallmark of cancer cells is accelerated glucose metabolism even in the presence of oxygen. Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose, thereby trapping it in the cell to be used in various downstream pathways. Previous research in our laboratory showed that while normal mammary gland cells do not express the hexokinase 2 (HK2) isoform, it is highly overexpressed in breast cancer cells, which is responsible for the accelerated glucose utilization. Hexokinase 2 deletion inhibits the tumorigenicity of cancer cells in vitro and in vivo, making it a good potential therapeutic target. However, metastasis accounts for the high mortality rate in breast cancer, so it is imperative to elucidate the possible role of HK2 expression in breast cancer metastasis. This study tests the innovative hypothesis that HK2 plays a role in breast cancer’s ability to metastasize. We demonstrate that systemic deletion of HK2 after tumor onset in a mouse model of breast cancer metastasis profoundly inhibits lung metastasis. Single cell RNA sequencing of the mouse primary tumors revealed that the loss of HK2 impaired the expression of genes important for the epithelial-mesenchymal transition (EMT) and metastasis. Mechanistically, HK2 expression appears to drive metastasis through altered gene expression by stabilizing SNAIL, a pro-EMT transcription factor. Additionally, HK2 expression appears to increase glucose availability for the flux through the oxidative pentose phosphate pathway to maintain a cellular redox state. Overall, this study provides evidence for a new therapeutic target for breast cancer metastasis.