Abstract 4106: Glutamine deficiency drives epigenetic silencing of <i>GLS2</i> to promote survival and metastasis from the core region of colorectal cancer

Abstract Rapid, uncontrolled proliferation is one representative hallmark of cancer. As tumor masses grow, the core regions receive inadequate blood supply, leading to severe nutrients and oxygen deprivation. Glutamine—regarded as non-essential for normal cells—has emerged as a critical nutrient that supports cancer cell metabolism. While glutamine deprivation typically induces cell death in the tumor core, some cancer cells survive by leveraging adaptive epigenetic mechanisms. However, the molecular mechanisms underlying this adaptation remain poorly understood. Using ATAC-seq and RNA-seq analyses, we revealed that glutamine deprivation induces the epigenetic silencing of GLS2, an enzyme that converts glutamine to glutamate, in colorectal cancer cells through increasing H3K27Me3 histone modification. This epigenetic silencing suppresses ferroptosis, an iron-dependent form of cell death, that enables cancer cells to survive and proliferate under glutamine-scarce conditions. With patient-derived colorectal cancer sample, we further confirmed a significant downregulation of GLS2 within the tumor core, specifically in regions that remained actively proliferative despite nutrient deprivation. Additionally, tumor core cells deprived of glutamine exhibited increased invasion and migration abilities, indicating an enhanced metastatic potential towards nutrient-rich compartments or distal sites. Treatment with histone methylation inhibitors successfully reversed GLS2 silencing, restored ferroptosis sensitivity, and suppressed metastatic behavior, which together emphasizes the potential of targeting epigenetic dysregulation as a therapeutic strategy. Combining epigenetic therapies to restore GLS2 expression with ferroptosis-inducing drugs offers a promising, integrative approach to target resilient cancer cells in nutrient-deprived tumor cores. This strategy holds significant clinical potential for improving outcomes in patients with aggressive colorectal cancer, particularly those exhibiting resistance to ferroptosis-targeting anticancer drugs due to metabolism reprogramming. Citation Format: Ji-Yeon Lee, So Hyun Kwon, Su Chan Park, Taehan Yoon, Jumi Kim, Hyunwoo Kim, Eun Jung Park, Ji Min Lee. Glutamine deficiency drives epigenetic silencing of GLS2 to promote survival and metastasis from the core region of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4106.