Silencing SGO2 by Oxamic Acid Dissociates Glycolysis and BRCA1-Mediated DNA Repair to Improve the Chemosensitivity of Lung Adenocarcinoma

Abstract

Aerobic glycolysis and DNA damage repair participate in modulating LUAD chemo sensitivity, while the connection between glycolysis and DNA repair is not fully discovered. Here, integrated multi-omics analyses recognized SGO2 as a glycolysis- and DNA repair-associated gene. SGO2 was up regulated in lung adenocarcinoma (LUAD) compared to normal controls and independently predicted poor prognosis in LUAD patients in three independent cohorts. In addition, SGO2 compromised the cisplatin (CDDP) sensitivity of LUAD in vitro and in vivo. Mechanistically, SGO2 interacted with BRCA1 to restrain BRCA1 ubiquitination and degradation, thereby enhancing homologous recombination repair signaling. Interestingly, a dietary bioactive compound, oxamic acid (OA) served as a glycolysis inhibitor to attenuate lactate (LA) production, thereby impairing histone H3 lysine 18 lactylation (H3K18la) and histone H3 lysine 27 acetylation (H3K27ac)-mediated chromatin accessibility to suppress SGO2 transcription. Furthermore, OA repressed SGO2/BRCA1-regulated homologous recombination repair signaling to mitigate LUAD progression and was presented as a therapeutic compound with no apparent toxicity in vivo. This study demonstrated that SGO2 is a downstream effector of glycolysis and an upstream regulator of DNA damage repair. Silencing SGO2 with OA improved LUAD chemo sensitivity. Our work highlights the potential of SGO2 as a target for therapeutic intervention and OA as a food-bioactive compound for LUAD treatment.

Keywords

histone lactylation / lung adenocarcinoma / oxamic acid / SGO2

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