# Metabolic syndrome promotes endometrial cancer by Oleic acid-mediated polyamine accumulation

## TL;DR

Metabolic syndrome increases endometrial cancer risk by causing fatty acid-driven polyamine buildup, offering new targets for treatment.

## Contribution

The study reveals a novel mechanism linking metabolic syndrome to endometrial cancer through oleic acid, HOXB9, and ODC1.

## Key findings

- Oleic acid stabilizes HOXB9, which prevents ODC1 degradation and increases polyamine levels.
- Targeting HOXB9 or ODC1 reduces tumor growth and increases chemosensitivity in patient-derived tumor cells.
- The oleic acid-HOXB9-ODC1 axis is confirmed in patient tissues, suggesting therapeutic potential.

## Abstract

Metabolic syndrome increases the risk of endometrial cancer development and progression, but the mechanism remains unclear. We find that polyamine metabolites are notably elevated in the sera and tumor tissues of endometrial cancer patients with metabolic syndrome. Oleic acid, one of the many components in hyperlipidemia, is the key factor for upregulating Ornithine Decarboxylase 1 (ODC1) (the rate-limiting enzyme in polyamine metabolism) and downstream polyamines. Mechanistically, Oleic acid binds to and stabilizes Homeobox B9 (HOXB9) by inhibiting the binding of HOXB9 to E3 ligase Praja2. Stable HOXB9 then competes with OAZ1 and combines with ODC1 to block ODC1 degradation. Targeting HOXB9 or ODC1 reduces polyamine levels and suppresses tumor growth/spread. Oleic acid-HOXB9-ODC1 stable cascading axis then is confirmed in patient tissues, and ODC1 inhibitors boost patient-derived tumor cells’ chemosensitivity. This study links fatty acids to polyamine buildup, reveals a mechanism for metabolic syndrome-driven endometrial cancer, and points to HOXB9 and ODC1 as potential therapeutic targets.

Metabolic syndrome (MS) is associated with enhanced risk to develop endometrial cancer (EC). Here, the authors show that oleic acid, increased in MS, promotes endometrial cancer by supporting the stability of the rate-limiting enzyme in polyamine metabolism ODC1 and polyamine accumulation.