Let-7b-5p inhibits breast cancer cell growth and metastasis via repression of hexokinase 2-mediated aerobic glycolysis

Abstract Hexokinase 2 (HK2), a critical rate-limiting enzyme in glycolytic pathway catalyzing hexose phosphorylation, is overexpressed in multiple human cancers, and associates with poor clinicopathological features. Drugs targeting aerobic glycolysis regulators, including HK2, are in development. However, physiological significance of HK2 inhibitors and mechanisms of HK2 inhibition in cancer cells remain largely unclear. Herein, we show that microRNA-let-7b-5p (let-7b-5p) represses HK2 expression by targeting its 3’-untranslated region. By suppressing HK2-mediated aerobic glycolysis, let-7b-5p restrains breast tumor growth and metastasis both in vitro and in vivo. In patients with breast cancer, let-7b-5p expression is significantly downregulated, and is negatively correlated with HK2 expression. Our findings indicate that let-7b-5p/HK2 axis plays a key role in aerobic glycolysis as well as breast tumor proliferation and metastasis, and targeting this axis is a potential therapeutic strategy for breast cancer.