HOXB7 is associated with oxaliplatin resistance in colon cancer through glutamine metabolic reprogramming via non-canonical activation of YAP1

Abstract Colon cancer relapse and resistance to oxaliplatin remain major clinical challenges. Here, we identify HOXB7 as upregulated in colon cancer tissues and oxaliplatin-resistant cell models, and associated with adverse survival outcomes. Functional studies in vitro and in vivo showed that HOXB7 promoted proliferation, glutamine metabolism, suppressed apoptosis, and reduced oxaliplatin sensitivity. Mechanistically, HOXB7 transcriptionally activated OTUB1, which in turn stabilized YAP1 by reducing its ubiquitination, thereby sustaining glutamine metabolism in a manner largely independent of canonical Hippo signaling. Genetic or pharmacological disruption of this pathway attenuated the HOXB7-driven resistant phenotype. Structure-based virtual screening identified Morin as a candidate small molecule associated with suppression of HOXB7 signaling. Morin suppressed the HOXB7–OTUB1–YAP1 axis, impaired glutamine metabolic activity, and restored oxaliplatin responsiveness in resistant colon cancer models. Collectively, these findings define an HOXB7–OTUB1–YAP1 signaling node that supports glutamine metabolic reprogramming and oxaliplatin resistance and suggest that suppression of HOXB7-associated signaling may represent a potential therapeutic strategy in oxaliplatin-refractory colon cancer.