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

Abstract

Metabolic activities are often accompanied by cell-cycle progression, yet known connections between these two processes remain limited. Here, we identified the isocitrate dehydrogenase 3β (IDH3β) 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), IDH3β was posttranslationally upregulated in late G₁ phase, and overexpression of IDH3β accelerated G₁-S transition, contributing to the promotion of cell proliferation <i>in vitro</i> and <i>in vivo</i>. α-Ketoglutarate (α-KG), a crucial metabolite in tricarboxylic acid (TCA) cycle, was dependent on IDH3β level and partially accounted for IDH3β-mediated cell growth. IDH3β expression increased PFKFB3 protein levels and enhanced glucose uptake, and high expression of IDH3β correlated with poor survival in patients with ESCC, suggesting a potential application of IDH3β 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 IDH3β 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.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/13/3281/F1.large.jpg.