e15732 Background: Colorectal adenocarcinoma (COAD) ranks as the third most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide. A major obstacle to successful chemotherapy for this malignancy is the development of resistance to oxaliplatin, a cornerstone chemotherapeutic agent. Intriguingly, recent studies have implicated the homeobox B cluster gene family in both oxaliplatin resistance and metabolic reprogramming. Based on this emerging evidence, we undertook the present study to investigate the specific role of HOXB7 in the development of oxaliplatin resistance in COAD. Methods: To explore the role of HOXB7, we first generated isogenic oxaliplatin-resistant CC cell lines and conducted analyses of clinical specimens. Then, we performed functional loss-of-experiments using knockdown approaches to assess the impact on proliferation, glutamine metabolism, and drug sensitivity. To decipher the underlying mechanism, we investigated the relationship between HOXB7, YAP1, and the deubiquitinase OTUB1 through overexpression rescue experiments and mechanistic studies. Furthermore, utilizing a structure-based virtual screening strategy of a high-throughput compound library, we sought to identify a potential HOXB7 inhibitor. The therapeutic potential of the identified compound, Morin, was then validated in patient-derived xenograft models. Results: Our analyses revealed that HOXB7 expression was significantly elevated in CC tissues compared with adjacent non-tumor tissues. Clinically, high HOXB7 expression was correlated with reduced disease-free survival in COAD patients. Functionally, in vitro knockdown of HOXB7 effectively suppressed CC cell proliferation, impaired glutamine metabolism, and consequently restored oxaliplatin sensitivity. Mechanistically, we discovered that HOXB7 upregulation increased YAP1 protein expression, and critically, overexpression of YAP1 reversed the phenotypic effects of HOXB7 knockdown. We further elucidated that HOXB7 transcriptionally upregulates the deubiquitinase OTUB1. OTUB1, in turn, stabilizes YAP1 protein via deubiquitination, ultimately enhancing glutamine metabolism through Hippo-independent pathways. Importantly, our drug screening efforts identified the FDA-approved drug Morin as a potent HOXB7 inhibitor and oxaliplatin sensitizer. This combination strategy demonstrated a significant enhancement of the antitumor effect of oxaliplatin in patient-derived xenograft models. Conclusions: This study elucidates a novel HOXB7-OTUB1-YAP1 axis that promotes chemoresistance in colon cancer by modulating glutamine metabolism. Our findings posit that targeting this pathway with the identified HOXB7 inhibitor, Morin, represents a promising and readily translatable therapeutic strategy for reversing oxaliplatin resistance in COAD patients.
Ye et al. (Thu,) studied this question.