The AMPK-HOXB9-KRAS axis regulates lung adenocarcinoma growth in response to cellular energy alterations.

Abstract

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.