CDH1 Orchestrates Anabolic Events to Promote Cell Cycle Initiation

Abstract Cell proliferation requires anabolic supports. How the cell cycle integrates anabolism remains poorly understood. Herein, it is identified that G1‐phase regulator cell division cycle 20‐like protein 1 (CDH1) coordinates anabolic events to ensure cell cycle initiation. CDH1 degrades Von Hippel–Lindau (VHL), concomitantly activates hypoxia‐inducible factor 1α (HIF1 α ), which enhances angiogenesis and glucose metabolism, and activates mitochondrial lactyltransferase alanyl tRNA synthetase (AARS2), which lactylates and inactivates pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), thereby conserving anabolites. Among the CDH1‐accumulated anabolites, ribose‐5‐phosphate (R5P) binds to transketolase‐like‐1 (TKTL1) to bridge CDH1 to cyclin‐dependent kinase 2 (CDK2) and Skp1‐Cullin‐F‐box and β ‐transducin repeat‐containing protein (SCF β ‐TRCP ) complex, thereby facilitating CDH1 phosphorylation and degradation to promote cell cycle initiation. This CDH1‐VHL‐HIF1 α /AARS2‐R5P/TKTL1 circuit is supported by the observation that low R5P levels and high CDH1 expression correlate with proliferating cancer cells and tissues. Moreover, it is demonstrated that an artificial R5P signal, generated by ribose‐5‐sulfate (R5S), sensitizes cancer cells to apoptosis by initiating the cell cycle in the absence of sufficient anabolite supply. These suggest that cancer signatures, including the Warburg effect and angiogenesis, are intrinsically driven by CDH1.