Abstract 7054: L1-ATP8B1 exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC

Abstract Long Interspersed Nuclear Element-1 (LINE-1, L1) plays important roles in carcinogenesis. However, the function of LINE-1 in lung squamous cell carcinoma (LUSC) remains unclear. Here we found that L1-ATP8B1 was overexpressed in LUSC patients with short survival and associated with mitochondrial dysfunction in both the TCGA dataset and the TJMUCH cohort. Overexpression of L1-ATP8B1 promoted cell proliferation and invasion in vitro and facilitated LUSC xenograft growth in vivo. L1-ATP8B1 affected mitochondrial complex enzyme I activity via affecting cardiolipin-dependent PHB1 sumoylation and promoting PHB1 ubiquitination, inducing high-level cellular reduction-oxidation (redox) homeostasis. Synergetic therapy with an L1 inhibitor and an antioxidant dramatically interfered with redox homeostasis and restored mitochondrial function, abolishing L1-ATP8B1-induced growth and metastasis of LUSC xenografts in vivo. In conclusion, we for the first time demonstrated that metabolic disorder plays a vital role in L1-related carcinogenesis and identified L1-ATP8B1 as a promising prognostic biomarker and therapeutic target for LUSC. Citation Format: Rui Zhang, Xiao Zhang, Zeguo Sun, Pengpeng Liu, Guidong Chen, Weijia Zhang, Jinpu Yu. L1-ATP8B1 exacerbates high-level reduction-oxidation homeostasis to promote carcinogenesis via affecting PHB1 sumoylation in LUSC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7054.