Arborinine from Glycosmis parva leaf extract inhibits clear-cell renal cell carcinoma by inhibiting KDM1A/UBE2O signaling

Abstract

Background: Arborinine is a natural product isolated from Globigerina parva (G. parva) leaf extract that shows strong anticancer activity with its role in clear-cell renal cell carcinoma (ccRCC) unreported. Objective: We aim to evaluate the role of Arborinine in ccRCC. Design: Arborinine was tested for its effects in ccRCC cell lines in vitro and in silico. Results: Arborinine conferred inhibitory effect to ccRCC cells at reasonable doses. Arborinine showed inhibitory effects on Lysine Demethylase 1A (KDM1A) in ccRCC cells and decreased levels of KDM1A outputs and on epithelial mesenchymal transition (EMT) markers. Arborinine significantly inhibited proliferation, apoptosis, and cell cycle progression and migration of ccRCC cells. Using in silico ChIP analysis and luciferase activity validation, we identified Ubiquitin-conjugating enzyme E2O (UBE2O) as an active transcription target down-stream of KDM1A. UBE2O expression was not only correlated with KDM1A expression but also associated with worsened prognosis in ccRCC. Overexpression of UBE2O abrogated cancer-inhibitory effect of Arborinine. Discussion: Arborinine holds promise as an additive in the treatment of ccRCC. Conclusions: We have shown for the first time that Arborinine showed inhibitory effect on ccRCC via KDM1A/ UBE2O signaling.