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

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Chemotherapy resistance is a major challenge in gastric cancer (GC) treatment.
• Increased cancer stemness contributes to chemotherapy resistance in GC.
• Oxaliplatin (OXA) is a key first-line chemotherapy agent for GC.

Purpose of the Study:

• To investigate the role of JMJD3 (encoded by KDM6B) in GC chemoresistance and stemness.
• To elucidate the molecular mechanisms by which JMJD3 affects GC malignancy.
• To explore JMJD3 as a potential therapeutic target for overcoming GC chemoresistance.

Main Methods:

• Assessed JMJD3 expression in GC tissues and patient-derived xenograft (PDX) models.
• Manipulated JMJD3 expression (overexpression and knockdown) in GC cells.
• Analyzed histone modification (H3K27me3) on the ALOX5 promoter.
• Utilized mouse models with Kdm6b deletion to study tumorigenesis.
• Investigated the effect of JMJD3 on ferroptosis sensitivity in GC cells.

Main Results:

• JMJD3 is highly expressed in GC tissues and chemoresistant PDX models.
• JMJD3 overexpression enhanced GC cell stemness and chemoresistance; knockdown had opposite effects.
• JMJD3 reduced H3K27me3 on the ALOX5 promoter, leading to its transcriptional activation.
• Gastric epithelial cell-specific Kdm6b deletion reduced MNU-induced tumorigenesis.
• Increased JMJD3/ALOX5 function sensitized GC cells to ferroptosis inducers.

Conclusions:

• JMJD3 plays a critical role in GC chemoresistance by promoting stemness and modulating ferroptosis sensitivity.
• Targeting JMJD3 presents a novel therapeutic strategy for overcoming GC chemotherapy resistance.
• Ferroptosis inducers may serve as a promising adjunctive treatment for GC when combined with JMJD3-targeting therapies.