APC/C-CDH1-Regulated IDH3β Coordinates with the Cell Cycle to Promote Cell Proliferation

Metabolic activities are often accompanied by cell-cycle progression, yet known connections between these two processes remain limited. Here, we identified the isocitrate dehydrogenase 3 beta (IDH3 beta) as a novel substrate of anaphase-promoting complex/cyclosome (APC/C)-CDH1 and an important regulator of the cell cycle. In esophageal squamous cell carcinoma (ESCC), IDH3 beta was posttranslationally upregulated in late G(1) phase, and overexpression of IDH3 beta accelerated G(1)-S transition, contributing to the promotion of cell proliferation in vitro and in vivo. alpha-Ketoglutarate (alpha-KG), a crucial metabolite in tricarboxylic acid (TCA) cycle, was dependent on IDH3 beta level and partially accounted for IDH3 beta-mediated cell growth. IDH3 beta expression increased PFKFB3 protein levels and enhanced glucose uptake, and high expression of IDH3 beta correlated with poor survival in patients with ESCC, suggesting a potential application of IDH3 beta in prognosis. Overall, our results highlight a new molecular connection between cell-cycle regulation and the TCA cycle in ESCC. Significance: These findings show that IDH3 beta is an APC/C-CDH1 substrate and is expressed in a cell-cycle-dependent manner, highlighting novel molecular cross-talk between the TCA cycle and cell cycle in cancer cells.