Deubiquitination of NICD1 by USP10 Restrains Esophageal Cancer: A Link Between NOTCH1 Stabilization, Oxidative Stress, and Ferroptosis

The development of new drugs and focused treatment strategies is significantly hampered by the inadequate understanding of the complex pathophysiology of esophageal cancer (EC). Significant risk factors for the development of EC include imbalances in the oxidative stress and anti-oxidative response pathways. It has been discovered that therapeutic interventions that target the ubiquitin-specific protease 10 (USP10) and its targeted response element in response to oxidative stress can inhibit tumour growth and provide notable clinical benefits for cancer patients. To determine if USP10 is a ubiquitin-specific protease that controls oxidative stress, which in turn stabilises NOTCH1 and deactivates the anti-oxidative transcription-related pathway, and to investigate the impact of USP10 on the development of EC. As a major endogenous stabiliser of NOTCH1 intracellular domain (NICD1) function, we recognized USP10 as a protein that interacts with NICD1 and catalyses the deubiquitination of NICD1 in EC cells. Loss of USP10 specific to epithelial cells interferes with NICD1 stabilisation, which in turn stimulates the production of antioxidant genes to prevent ferroptosis caused by lipid peroxidation and significantly accelerates the development of esophageal cancer. On the other hand, in animal models treated with 4-NQO, transgenic overexpression-mediated USP10 gene therapy reduces the development of esophageal cancer. Mechanistically, USP10 binds to NICD1 in response to oxidative stress, deconjugates ubiquitination chains, and increases NICD1 abundance and the activation of its downstream signalling cascade. In vivo investigations have also shown that inhibiting USP10 expression significantly reduces the impacts that cause cancer. Importantly, a bad prognosis is indicated by reduced expression of USP10, which is linked to the severity of EC. According to these results, USP10 might be a suitable therapeutic target for the treatment of esophageal cancer.