OA-HOXB9-ODC1-Polyamine Axis Mediates Metabolic Syndrome Promoting Endometrial Cancer Progression

Metabolic syndrome (MS) is a risk factor for both the development and progression of endometrial cancer (EC); however, the mechanism remains unclear. We found that polyamine metabolites are significantly elevated in the sera and tumor tissues of EC patients with MS (ECWMS). Hyperlipidemia is a critical factor in promoting ECWMS, and oleic acid (OA), an important monounsaturated fatty acid, was identified from 12 common fatty acids as a crucial element in upregulating ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine metabolism, and downstream polyamines in the plasma of ECWMS. Mechanistically, OA binds directly to HOXB9 and stabilizes it by preventing its interaction with E3 ligases Praja2. HOXB9 further interacts with ODC1 and competes with the interaction between ornithine decarboxylase antizyme 1 (OAZ1) and ODC1 for proteasomal degradation. The downstream accumulation of polyamine metabolites, especially putrescine, further inhibits the degradation of HOXB9. Targeting the feedback of the HOXB9-ODC1-polyamine axis decreases polyamines and inhibits tumor proliferation and metastasis in vitro and in vivo. Multiplex immunofluorescence staining, liquid chromatography-mass spectrometry (LC-MS), and Raman spectroscopy all demonstrate that the OA-HOXB9-ODC1-polyamine axis is present in ECWMS tissues, and ODC1 inhibitors effectively enhance the sensitivity of patient-derived tumor cells (PTCs) to chemotherapeutic drugs. This study links fatty acid levels to polyamine accumulation, ultimately promoting EC progression and revealing the mechanism by which MS promotes EC progression. Targeting HOXB9 or ODC1 is expected to be a potential therapeutic strategy to control patients with MS-related progressive, drug-resistant, or relapsed EC.