Abstract

Summary HOXB9 is an important transcription factor associated with unfavorable outcomes in patients with lung adenocarcinoma (LUAD). However, its degradation mechanism remains unclear. Here, we show that HOXB9 is a substrate of AMP kinase alpha (AMPKα). AMPK mediates HOXB9 T133 phosphorylation and downregulates the level of HOXB9 in mice and LUAD cells. Mechanistically, phosphorylated HOXB9 promoted E3 ligase Praja2-mediated HOXB9 degradation. Blocking HOXB9 phosphorylation by depleting AMPKα1/2 or employing the HOXB9 T133A mutant promoted tumor cell growth in cell culture and mouse xenografts via upregulation of HOXB9 and KRAS that is herein identified as a target of HOXB9. Clinically, AMPK activation levels in LUAD samples were positively correlated with pHOXB9 levels; higher pHOXB9 levels were associated with better survival of patients with LUAD. We thus present a HOXB9 degradation mechanism and demonstrate an AMPK-HOXB9-KRAS axis linking glucose-level-regulated AMPK activation to HOXB9 stability and KRAS gene expression, ultimately controlling LUAD progression.