Abstract LB299: Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer

Abstract

Abstract Dihydrouridine is a universally conserved tRNA modification installed by enzymes that are important for human health. High expression of dihydrouridine synthase 2 (DUS2) predicts poor patient outcomes in lung adenocarcinoma (LUAD) for reasons that are not yet clear. Here, we show in human cells and mouse xenografts that DUS2 suppresses ferroptosis, a metal-dependent non-apoptotic form of cell death that is emerging as a therapeutic target in lung cancer. Elevated DUS2 correlates with resistance to ferroptosis inducers and loss of DUS2 causes increased sensitivity with concomitant accumulation of toxic lipid peroxides. Mechanistically, DUS2 is required to maintain tRNA CysGCA levels, supporting translation of cysteine-rich proteins including metallothioneins, key regulators of metal and redox homeostasis Notably, DUS2 KO cells cannot sustain normal levels of metallothioneins, a class of very cysteine rich proteins that serve as key regulators of both metal and redox homeostasis. Accordingly, DUS2 knockout cells are more susceptible to zinc intoxication and have lower levels of reduced glutathione, which partially explains their sensitivity to ferroptosis. Our findings demonstrate that DUS2 is required to support tRNACys levels and fend off ferroptosis in lung cancer cells. This highlights that individual tRNA substrates can play an outsized role in the biological functions of tRNA modifying enzymes, and demonstrates the therapeutic potential of targeting DUS2 in cancer. Citation Format: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert. Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB299.