Rev-erbα deletion promotes gastric cancer progression through attenuating DLAT and DLST induced cuproptosis

Abstract

Background Cuproptosis is a unique copper-dependent cell death pathway. Nuclear receptor subfamily 1 group D member 1 (NR1D1/Rev-erbα) is a ligand-activated transcriptional regulator that is involved in regulating the development of circadian rhythm, lipid metabolism and immunity-associated diseases including cancer. However, the role of Rev-erbα in cuproptosis of gastric cancer (GC) cells remains poorly understood. Methods Functional assays both in vivo and in vitro were employed to explore the role of Rev-erbα on cell progression and cuproptosis, and its regulatory mechanism. Moreover, clinicopathological retrospective analysis explored the relationship of Rev-erbα with DLAT and DLST. Results Rev-erbα deletion promoted GC progression through cuproptosis. The Rev-erbα activator, GSK4112, inhibited GC progression through cuproptosis, and obtained a synergistical inhibitory effect with elesclomol. Mechanistically, Rev-erbα deletion promoted dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide S-succinyltransferase (DLST) expression through inhibiting DLAT oligomerization. Notably, this regulation was dependent on the DNA-binding domain (DBD) of Rev-erbα. Moreover, the combination of GSK4112 with elesclomol inhibited DLAT and DLST expression, and Rev-erbα SUMOylation. Furthermore, DLAT and DLST expression levels were associated with histological grade and tumor-node-metastasis stage in patients with GC. Thus, DLAT or DLST expression exhibit potential as independent biomarkers for predicting the prognosis of patients with GC. In addition, Rev-erbα expression was negatively correlated with DLAT and DLST expression, and high Rev-erbα and low DLAT expression, or high Rev-erbα and low DLST let to optimal levels of disease-free survival in patients with GC. Conclusion Rev-erbα exhibits potential in the treatment of GC.