# JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer

## TL;DR

This study shows that JMJD3 promotes gastric cancer malignancy and resistance to chemotherapy while making cancer cells more sensitive to ferroptosis, suggesting new treatment strategies.

## Contribution

The study reveals a novel role of JMJD3 in modulating stemness and ferroptosis sensitivity in gastric cancer.

## Key findings

- JMJD3 overexpression increases malignancy and chemoresistance in gastric cancer cells.
- ALOX5 upregulation by JMJD3 sensitizes cancer cells to ferroptosis inducers.
- Deleting Kdm6b in mice reduces MNU-induced tumorigenesis.

## Abstract

Chemotherapy remains the cornerstone of gastric cancer (GC) treatment, with Oxaliplatin (OXA) being a critical first-line agent. However, chemotherapy resistance, compounded by increased stemness, poses a significant challenge in GC management. In this study, we demonstrate that JMJD3, encoded by KDM6B and catalyzing the demethylation of H3K27me3, is highly expressed in both GC tissues and patient-derived chemotherapy-resistant xenograft (PDX) models and contributes to increased malignancy and chemoresistance. Overexpression of JMJD3 enhanced stemness and chemoresistance in GC cells, while JMJD3 knockdown had opposite effects. Mechanistically, JMJD3 promotes GC cell stemness and chemoresistance by reducing H3K27me3 on the ALOX5 promoter, a histone modification associated with ALOX5 transcriptional activation. Tumorigenesis induced by N-methyl-N-nitrosourea (MNU) was reduced in mice with gastric epithelial cell-specific deletion of Kdm6b. Importantly, ALOX5 upregulation due to the elevated JMJD3 function sensitized GC cells to ferroptosis inducers. These findings suggest that JMJD3 plays a pivotal role in GC chemoresistance by modulating both stemness and ferroptosis sensitivity. Targeting JMJD3 may provide a novel therapeutic strategy for overcoming chemotherapy resistance, with ferroptosis inducers potentially offering a promising adjunctive treatment in GC.